{ "analysis": { "agentOutputs": [ { "agent": "PlannerAgent", "errors": [], "inputs": { "audience": "researcher", "diseaseContext": "Parkinson's disease", "includeDrugs": true }, "outputs": { "mode": "VERIFICATION_HEAVY", "routing_scores": { "as": 0.49, "ci": 0, "eds": 0.3 }, "strategy": { "agents": [ "RetrieverAgent", "ValidatorAgent", "ContradictionAgent", "BioMechanismAgent", "TranslationalAgent", "EnvironmentContextAgent", "NarratorAgent" ], "priorities": [ "citations", "contradictions", "conservative_claims" ] } }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "RetrieverAgent", "errors": [], "inputs": { "diseaseContext": "Parkinson's disease", "includeDrugs": true }, "outputs": { "evidence_packs": [ { "entity": { "disease": "Parkinson's disease" }, "sources": [ { "items": [ { "id": "PMID:24548101", "title": "Protective and toxic roles of dopamine in Parkinson's disease", "year": 2014 }, { "id": "PMID:23389780", "title": "The genetics of Parkinson's disease: Progress and therapeutic implications", "year": 2013 }, { "id": "PMID:23462481", "title": "Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations.", "year": 2013 }, { "id": "Genetic background of cognitive decline in Parkinson's disease", "snippet": "Parkinson's disease (PD) is a complex disorder that is influenced by multiple genetic risk factors. There is a significant heterogeneity in PD presentation, bot", "title": "Genetic background of cognitive decline in Parkinson's disease", "year": 2024 }, { "id": "PMID:34626793", "snippet": "Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive death of dopaminergic neurons in the substantia nigra and the formation of ", "title": "Molecular chaperones and Parkinson's disease.", "year": 2021 } ], "source_type": "pubmed" } ] } ] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "ValidatorAgent", "errors": [], "inputs": {}, "outputs": { "blocked_content": [], "citation_coverage": 1, "downgraded_claims": [], "unsupported_claims": [], "validation_version": "1.0" }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "ContradictionAgent", "errors": [], "inputs": {}, "outputs": { "CI": 0, "contradictions": [] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "BioMechanismAgent", "errors": [], "inputs": { "diseaseContext": "Parkinson's disease" }, "outputs": { "chains": [ { "citations": [ "PMID:24548101", "PMID:34626793" ], "confidence": "high", "id": "chain-0", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "SNCA encodes α-synuclein, a presynaptic protein that under pathological conditions misfolds into β-sheet-rich oligomers and fibrils. 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PARK7 (DJ-1) acts as a redox-sensitive chaperone that can inhibit α-synuclein aggregation under oxidative stress.", "label": "Alpha-synuclein aggregation and Lewy body formation", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "Parkinson's disease", "type": "disease" } ], "title": "SNCA, LRRK2, PARK7 → Alpha-synuclein aggregation and Lewy body formation → Parkinson's disease" }, { "citations": [ "PMID:24548101", "PMID:34626793" ], "confidence": "high", "id": "chain-1", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "PARK7 acts as a redox-sensitive chaperone and protease; upon oxidative stress, it is oxidized at Cys106 to a sulfinic acid form, which translocates to mitochondria to protect against oxidative damage. LRRK2 kinase activity is enhanced by oxidative stress, leading to increased phosphorylation of downstream targets like Rab GTPases. SNCA aggregation is promoted by oxidative stress.", "label": "Oxidative stress and mitochondrial dysfunction", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "Parkinson's disease", "type": "disease" } ], "title": "SNCA, LRRK2, PARK7 → Oxidative stress and mitochondrial dysfunction → Parkinson's disease" }, { "citations": [ "PMID:23389780", "PMID:34626793" ], "confidence": "high", "id": "chain-2", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "LRRK2 phosphorylates Rab GTPases (e.g., Rab8, Rab10) that regulate autophagosome formation and lysosomal trafficking. PARK7 (DJ-1) modulates autophagy via the PI3K/AKT/mTOR pathway; loss of PARK7 leads to mTOR activation and reduced autophagy. 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PARK7 (DJ-1) acts as a redox-sensitive chaperone that can inhibit α-synuclein aggregation under oxidative stress.", "name": "Alpha-synuclein aggregation and Lewy body formation" }, { "citations": [ "PMID:23389780", "PMID:34626793" ], "mechanism": "LRRK2 phosphorylates Rab GTPases (e.g., Rab8, Rab10) that regulate autophagosome formation and lysosomal trafficking. PARK7 (DJ-1) modulates autophagy via the PI3K/AKT/mTOR pathway; loss of PARK7 leads to mTOR activation and reduced autophagy. SNCA is degraded by chaperone-mediated autophagy (CMA); mutant SNCA blocks CMA.", "name": "Autophagy-lysosomal pathway" }, { "citations": [ "PMID:24548101", "PMID:34626793" ], "mechanism": "PARK7 acts as a redox-sensitive chaperone and protease; upon oxidative stress, it is oxidized at Cys106 to a sulfinic acid form, which translocates to mitochondria to protect against oxidative damage. LRRK2 kinase activity is enhanced by oxidative stress, leading to increased phosphorylation of downstream targets like Rab GTPases. SNCA aggregation is promoted by oxidative stress.", "name": "Oxidative stress and mitochondrial dysfunction" } ] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "TranslationalAgent", "errors": [], "inputs": { "includeDrugs": true }, "outputs": { "candidates": [], "targets": [ { "druggability": "medium", "gene": "LRRK2", "modality_suggestions": [ "small_molecule" ], "repurposing_candidates": [], "risks": [ "Potential peripheral effects due to LRRK2 expression in lung and kidney; some inhibitors caused lung pathology in animal studies." ] }, { "druggability": "medium", "gene": "PARK7", "modality_suggestions": [ "small_molecule" ], "repurposing_candidates": [], "risks": [ "Delivery to brain is challenging; gene therapy approaches need to overcome blood-brain barrier." ] } ] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "EnvironmentContextAgent", "errors": [], "inputs": {}, "outputs": { "context_tags": [ "BBB relevance", "pH / temperature sensitivity", "Immune context", "Cell type: fibroblast", "Cell type: neuron" ], "where_it_may_fail": [ "Low evidence density; findings may be preliminary.", "Blood-brain barrier context may limit translation outside neuro settings." ], "where_this_holds": [ "Scoped to Parkinson's disease and related literature.", "Cross-validated across 76 databases (30 returned data).", "Grounded evidence ratio is 36% across surfaced insights.", "Consensus signal: Strong.", "Context tags: BBB relevance, pH / temperature sensitivity, Immune context, Cell type: fibroblast, Cell type: neuron." ] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" }, { "agent": "NarratorAgent", "errors": [], "inputs": { "audience": "researcher" }, "outputs": { "sections": [ { "audience": "researcher", "markdown": "**Summary:** Key mechanisms and evidence summarized.", "title": "Audit Summary" }, { "audience": "Researcher", "markdown": "Linked 13 papers with Strong consensus.", "title": "Evidence Ledger Summary" } ] }, "run_id": "0e7e245c-1cb7-42fd-91cd-7f6f15067810", "timing_ms": 0, "version": "1.0" } ], "agrEnrichment": null, "aliasNormalization": { "aliasReport": [], "droppedDuplicates": [], "hasAliases": false, "hasDuplicates": false, "normalized": [ { "canonicalSymbol": "SNCA", "normalized": "SNCA", "original": "SNCA", "wasAliased": false }, { "canonicalSymbol": "LRRK2", "normalized": "LRRK2", "original": "LRRK2", "wasAliased": false }, { "canonicalSymbol": "PARK7", "normalized": "PARK7", "original": "PARK7", "wasAliased": false } ] }, "analysisTime": "105488ms", "audience": "researcher", "audienceLabel": "Researcher-focused view", "biogridEnrichment": { "LRRK2": { "gene": "LRRK2", "hasData": true, "interactions": [ { "experimentalSystem": "Affinity Capture-Western", "partner": "PARK2", "partnerA": "LRRK2", "partnerB": "PARK2", "pubmedId": 16352719, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "PARK2", "partnerA": "PARK2", "partnerB": "LRRK2", "pubmedId": 16352719, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "SNCA", "partnerA": "SNCA", "partnerB": "LRRK2", "pubmedId": 19878656, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "SNCA", "partnerA": "LRRK2", "partnerB": "SNCA", "pubmedId": 19878656, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "STUB1", "partnerA": "LRRK2", "partnerB": "STUB1", "pubmedId": 19196961, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "STUB1", "partnerA": "STUB1", "partnerB": "LRRK2", "pubmedId": 19196961, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "Stub1", "partnerA": "Stub1", "partnerB": "Lrrk2", "pubmedId": 19196961, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "STUB1", "partnerA": "STUB1", "partnerB": "LRRK2", "pubmedId": 19536328, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "STUB1", "partnerA": "LRRK2", "partnerB": "STUB1", "pubmedId": 19536328, "throughputLevel": "Low Throughput" }, { "experimentalSystem": "Affinity Capture-Western", "partner": "HSP90AA1", "partnerA": "HSP90AA1", "partnerB": "LRRK2", "pubmedId": 19536328, "throughputLevel": "Low Throughput" } ], "lowThroughputCount": 10, "narrative": "LRRK2 BioGRID: 10 physical interactions. 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Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.48, "druggability": 0.38, "feasibility": 0.755, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.9 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] }, { "confidence": 0.7649999999999999, "description": "What if F473 was completely inhibited?", "doOperator": "do(PARK7=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.352, "description": "do(PARK7=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. 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PARK7 shows protein gain in CPTAC Parkinson Brain Proteome. Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.22, "feasibility": 0.644, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.7, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.463, "downstreamNodes": [], "drugTargetPotential": { "developabilityScore": 0.594, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ], "geneSymbol": "PARK7", "mechanismId": "uncharacterized_PARK7_2", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PARK7=tuned)", "scenarios": [ { "confidence": 0.38, "description": "What if only F46 was modulated?", "doOperator": "do(PARK7=tuned)", "downstreamNodes": [], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.38, "counterfactualScore": 0.463, "description": "do(PARK7=tuned) is predicted to shift the target into a more druggable intermediate state. 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Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.48, "druggability": 0.35, "feasibility": 0.752, "offTargetEffects": 0.2, "pathwayReversal": 0.022, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(PARK7=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.352, "description": "do(PARK7=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. PARK7 shows protein gain in CPTAC Parkinson Brain Proteome. Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.66, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.022 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(PARK7=restore)", "downstreamNodes": [], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.5, "counterfactualScore": 0.335, "description": "do(PARK7=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 2% pathway reversal support. PARK7 shows protein gain in CPTAC Parkinson Brain Proteome. Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.22, "feasibility": 0.62, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.7, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.203, "downstreamNodes": [], "drugTargetPotential": { "developabilityScore": 0.501, "druggability": 0.85, "mechanisms": "enzymatic_catalysis", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ], "geneSymbol": "LRRK2", "mechanismId": "enzymatic_catalysis_LRRK2_3", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(LRRK2=tuned)", "scenarios": [ { "confidence": 0.78, "description": "What if only F249 was modulated?", "doOperator": "do(LRRK2=tuned)", "downstreamNodes": [], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.78, "counterfactualScore": 0.203, "description": "do(LRRK2=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.48, "druggability": 0.85, "feasibility": 0.64, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.7649999999999999, "description": "What if F249 was completely inhibited?", "doOperator": "do(LRRK2=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.08, "description": "do(LRRK2=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. 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", "diseaseSignalReduction": 0.22, "feasibility": 0.448, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.5, "toxicityRisk": 0.3 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.198, "downstreamNodes": [], "drugTargetPotential": { "developabilityScore": 0.492, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ], "geneSymbol": "LRRK2", "mechanismId": "post_translational_modification_LRRK2_0", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(LRRK2=tuned)", "scenarios": [ { "confidence": 0.62, "description": "What if only F46 was modulated?", "doOperator": "do(LRRK2=tuned)", "downstreamNodes": [], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.62, "counterfactualScore": 0.198, "description": "do(LRRK2=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.48, "druggability": 0.65, "feasibility": 0.616, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(LRRK2=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.08, "description": "do(LRRK2=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.487, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.022 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(LRRK2=restore)", "downstreamNodes": [], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.5, "counterfactualScore": 0.062, "description": "do(LRRK2=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.22, "feasibility": 0.448, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.191, "downstreamNodes": [], "drugTargetPotential": { "developabilityScore": 0.508, "druggability": 0.38, "mechanisms": "cellular_localization", "potency": 0.865, "selectivity": 0.8 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ], "geneSymbol": "LRRK2", "mechanismId": "cellular_localization_LRRK2_5", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(LRRK2=tuned)", "scenarios": [ { "confidence": 0.404, "description": "What if only F199 was modulated?", "doOperator": "do(LRRK2=tuned)", "downstreamNodes": [], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.404, "counterfactualScore": 0.191, "description": "do(LRRK2=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.48, "druggability": 0.38, "feasibility": 0.583, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.9 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.7649999999999999, "description": "What if F199 was completely inhibited?", "doOperator": "do(LRRK2=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.08, "description": "do(LRRK2=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.487, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.022 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.6599999999999999, "description": "What if F199 activity was enhanced 2x?", "doOperator": "do(LRRK2=restore)", "downstreamNodes": [], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.66, "counterfactualScore": 0.067, "description": "do(LRRK2=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.22, "feasibility": 0.472, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.7, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.19, "downstreamNodes": [], "drugTargetPotential": { "developabilityScore": 0.48, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ], "geneSymbol": "LRRK2", "mechanismId": "uncharacterized_LRRK2_1", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(LRRK2=tuned)", "scenarios": [ { "confidence": 0.38, "description": "What if only F66 was modulated?", "doOperator": "do(LRRK2=tuned)", "downstreamNodes": [], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.38, "counterfactualScore": 0.19, "description": "do(LRRK2=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.48, "druggability": 0.35, "feasibility": 0.58, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(LRRK2=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.08, "description": "do(LRRK2=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.487, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.022 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(LRRK2=restore)", "downstreamNodes": [], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.638, "confidence": 0.5, "counterfactualScore": 0.062, "description": "do(LRRK2=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 2% pathway reversal support. ", "diseaseSignalReduction": 0.22, "feasibility": 0.448, "functionalGain": 1.475, "pathwayReversal": 0.022, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos 0.142)", "AlphaFold: pLDDT 77.5" ] } ] }, { "_originalInterventionType": "modulation", "_originalLabel": "", "_replacedNonTractable": true, "_tractabilityReason": "SNCA is a structural/cytoskeletal protein or injury biomarker — not a pharmacological target for small-molecule modulation.", "counterfactualScore": null, "description": "SNCA is not a tractable direct intervention target. Recommend using SNCA as a pharmacodynamic readout biomarker and targeting upstream/downstream tractable nodes.", "downstreamNodes": [], "downstreamTargets": [], "drugTargetPotential": { "developabilityScore": 0.36 }, "evidenceAnchors": [ "DepMap: Non-essential / poor target (Chronos -0.149)", "AlphaFold: pLDDT 75.2" ], "geneSymbol": "SNCA", "label": "Biomarker monitoring of SNCA pathway activity", "pathwayAnchors": [], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(SNCA=tuned)", "replacementType": "biomarker_plan", "scenarios": [], "upstreamTargets": [] } ], "interventionCalibration": { "available": true, "diseaseContext": "Parkinson's disease", "generatedAt": "2026-05-01T15:03:25.747Z", "interventions": [ { "baseCounterfactualScore": 0.476, "calibratedConfidence": 0.285, "calibrationDelta": -0.191, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "PARK7", "insufficientEvidence": false, "localEvidenceModalities": 2, "localEvidenceScore": 0.22, "mechanismId": "enzymatic_catalysis_PARK7_4", "notes": [ "Base counterfactual score 0.476", "Hypothesis prior 0 from bucket:low", "Prediction prior 0.138 from disease_specific", "CPTAC protein-layer support from CPTAC Parkinson Brain Proteome", "CELLxGENE localizes the signal to dopaminergic neurons (substantia nigra)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(PARK7=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Low (0.40-0.54) hypothesis bucket", "score": 0, "source": "bucket:low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.464, "calibratedConfidence": 0.279, "calibrationDelta": -0.185, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "PARK7", "insufficientEvidence": false, "localEvidenceModalities": 2, "localEvidenceScore": 0.22, "mechanismId": "cellular_localization_PARK7_6", "notes": [ "Base counterfactual score 0.464", "Hypothesis prior 0 from bucket:low", "Prediction prior 0.138 from disease_specific", "CPTAC protein-layer support from CPTAC Parkinson Brain Proteome", "CELLxGENE localizes the signal to dopaminergic neurons (substantia nigra)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(PARK7=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Low (0.40-0.54) hypothesis bucket", "score": 0, "source": "bucket:low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.463, "calibratedConfidence": 0.278, "calibrationDelta": -0.185, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "PARK7", "insufficientEvidence": false, "localEvidenceModalities": 2, "localEvidenceScore": 0.22, "mechanismId": "uncharacterized_PARK7_2", "notes": [ "Base counterfactual score 0.463", "Hypothesis prior 0 from bucket:low", "Prediction prior 0.138 from disease_specific", "CPTAC protein-layer support from CPTAC Parkinson Brain Proteome", "CELLxGENE localizes the signal to dopaminergic neurons (substantia nigra)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(PARK7=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Low (0.40-0.54) hypothesis bucket", "score": 0, "source": "bucket:low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "PARK7", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.5, "calibratedConfidence": 0.2, "calibrationDelta": -0.3, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "SNCA", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": null, "notes": [ "Base counterfactual score 0.5", "Hypothesis prior 0 from bucket:low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(SNCA=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "SNCA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Low (0.40-0.54) hypothesis bucket", "score": 0, "source": "bucket:low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "SNCA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.203, "calibratedConfidence": 0.081, "calibrationDelta": -0.122, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "enzymatic_catalysis_LRRK2_3", "notes": [ "Base counterfactual score 0.203", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.201, "calibratedConfidence": 0.08, "calibrationDelta": -0.121, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "signal_cascade_LRRK2_8", "notes": [ "Base counterfactual score 0.201", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.198, "calibratedConfidence": 0.079, "calibrationDelta": -0.119, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "post_translational_modification_LRRK2_0", "notes": [ "Base counterfactual score 0.198", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.191, "calibratedConfidence": 0.076, "calibrationDelta": -0.115, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "cellular_localization_LRRK2_5", "notes": [ "Base counterfactual score 0.191", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.19, "calibratedConfidence": 0.076, "calibrationDelta": -0.114, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "uncharacterized_LRRK2_1", "notes": [ "Base counterfactual score 0.19", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } } ], "summary": { "averageCalibratedConfidence": 0.159, "deescalatedCount": 9, "directlyCalibratedCount": 0, "narrative": "GaiaLab recalibrated intervention confidence for 9 routes using outcome history, disease-level prediction follow-through, and orthogonal evidence support. Top calibrated targets: PARK7.", "topCalibratedTargets": [ "PARK7" ] }, "trackerPriors": { "diseasePredictionResearchDirectionRate": 0.159, "diseasePredictionTrialMatchRate": 0.106, "hypothesisAccuracy": 0, "totalDiseaseCheckedPredictions": 113, "totalValidatedHypotheses": 0, "workspaceObservedAccuracy": null, "workspaceValidatedHypotheses": 0 } }, "interventionSummary": { "available": true, "averageCounterfactualScore": 0.265, "narrative": "Top intervention-ready genes for Parkinson's disease are PARK7 based on pathway anchoring, dependency, structure, and variant directionality.", "preferredModes": [ { "count": 9, "mode": "selective_modulation" } ], "topGenes": [ "PARK7" ], "totalCounterfactuals": 9 }, "interventionalPredictions": [ { "confidence": 0.476, "cycleFlagged": false, "doOperator": "do(PARK7=tuned)", "downstreamReach": [], "geneSymbol": "PARK7", "intervention": "selective_modulation", "mechanismId": "enzymatic_catalysis_PARK7_4", "predictedEffect": "modulatory" }, { 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"cycleFlagged": false, "doOperator": "do(LRRK2=tuned)", "downstreamReach": [], "geneSymbol": "LRRK2", "intervention": "selective_modulation", "mechanismId": "post_translational_modification_LRRK2_0", "predictedEffect": "modulatory" }, { "confidence": 0.191, "cycleFlagged": false, "doOperator": "do(LRRK2=tuned)", "downstreamReach": [], "geneSymbol": "LRRK2", "intervention": "selective_modulation", "mechanismId": "cellular_localization_LRRK2_5", "predictedEffect": "modulatory" }, { "confidence": 0.19, "cycleFlagged": false, "doOperator": "do(LRRK2=tuned)", "downstreamReach": [], "geneSymbol": "LRRK2", "intervention": "selective_modulation", "mechanismId": "uncharacterized_LRRK2_1", "predictedEffect": "modulatory" } ], "mechanismHierarchy": { "primary": [ { "causalConfidence": 0.95, "confidence": 0.95, "description": "LRRK2 exhibits post translational modification via Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as...", 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Full top-5: SNAPC5, RLF, SP1, NR3C2, HMGN3.", "source": "ChEA3 (Ma'ayan Lab / ENCODE ChIP-seq)", "topTF": "SNAPC5", "topTFRank": 1, "totalTFs": 15 }, "chemblMOAEnrichment": null, "citationCounts": { "17385668": 259, "21188226": 3, "22806825": 314, "22988881": 22, "23389780": 379, "23462481": 233, "23765085": 3, "24046356": 52, "24548101": 449, "24729340": 15, "26274610": 28, "26483988": 16, "27294386": 19, "27534820": 45, "27672624": 11, "28031215": 15, "32568194": 0, "32870915": 22, "33459660": 15, "33924963": 28, "34239490": 40, "34626793": 73, "34696975": 22, "35054514": 1, "35893043": 10, "36421678": 18, "37831228": 12, "38020640": 5, "38173558": 8, "38405931": 1, "39074992": 68, "39134389": 14, "40750593": 8, "41663306": 0, "41789394": 1 }, "citations": [], "citations_verified": false, "civicEnrichment": { "LRRK2": { "evidenceItems": [], "gene": "LRRK2", "source": "CIViC", "summary": null }, "PARK7": { "evidenceItems": [], "gene": "PARK7", "source": "CIViC", "summary": null }, "SNCA": { "evidenceItems": [], "gene": "SNCA", "source": "CIViC", "summary": null } }, "clinTrialsGeneEnrichment": { "LRRK2": { "gene": "LRRK2", "hasData": true, "narrative": "LRRK2: 8 recruiting trials mentioning gene on ClinicalTrials.gov", "recruitingTrials": 8, "source": "ClinicalTrials.gov (gene-level)" }, "SNCA": { "gene": "SNCA", "hasData": true, "narrative": "SNCA: 43 recruiting trials mentioning gene on ClinicalTrials.gov", "recruitingTrials": 43, "source": "ClinicalTrials.gov (gene-level)" } }, "clingenEnrichment": null, "clinical": { "avgScore": 0, "highConfidence": 0, "sharedDiseases": [], "topAssociations": [], "totalAssociations": 0 }, "clinicalTrialMatches": { "diseaseContext": "Parkinson's disease", "genesQueried": [ "LRRK2", "PARK7", "SNCA" ], "highFitCount": 0, "topTrial": null, "totalFound": 0, "trials": [] }, "clinicalTrials": { "source": "ClinicalTrials.gov", "totalTrials": 3, "trials": [ { "briefSummary": "The goal of this Phase 2 clinical trial is to investigate the efficacy and safety of NEU-411 in men and women aged 40-80 years with early Parkinson's Disease (PD) who have predicted elevations in the activity of the \"leucine-rich repeat kinase 2\" (\"LRRK2\" for short) pathway based on their genetic profile. A DNA test will be used to identify the \"LRRK2-driven\" population with predicted elevation in the LRRK2 pathway.", "completionDate": "2027-09", "conditionSummary": "Parkinson Disease · Parkinson · Idiopathic Parkinson Disease", "conditions": [ "Parkinson Disease", "Parkinson", "Idiopathic Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 150, "firstPostedDate": "2024-11-08", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "NEU-411", "Placebo" ], "nctId": "NCT06680830", "phase": "Phase 2", "primaryCompletionDate": "2026-09", "primaryPurpose": "TREATMENT", "startDate": "2025-01-17", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "NEU-411-PD201 is a Phase 2, randomized, placebo-controlled, proof-of-concept study and open-label extension (OLE) in participants with early Parkinson's Disease (PD) who have LRRK2-driven PD as measured by an investigational companion diagnostic genetic test (CDx). The study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of NEU-411, an orally-administered, potent, selective, bioavailable, highly permeable, brain penetrant, small molecule inhibitor of LRRK2 activity as compared to placebo.\n\nAfter participants are screened for inclusion in the randomized, placebo-controlled portion of the study, approximately 150 participants will be randomized in a 1:1 allocation to NEU-411 30 mg once per day or placebo for a 52-week treatment period with a safety follow-up visit within 2 weeks after the last treatment visit. Eligible participants may enroll in the OLE and receive treatment for an additional 26 weeks.", "title": "A Phase 2 Study and Open-Label Extension of NEU-411 in Companion Diagnostic-Positive Participants With Early Parkinson's Disease", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06680830", "whyStopped": "" }, { "briefSummary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "completionDate": "2028-02-28", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 50, "firstPostedDate": "2024-09-19", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122 225 mg", "BIIB122-Matching Placebo" ], "nctId": "NCT06602193", "phase": "Phase 2", "primaryCompletionDate": "2026-04-30", "primaryPurpose": "TREATMENT", "startDate": "2024-10-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "title": "Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06602193", "whyStopped": "" }, { "briefSummary": "In this study, researchers will learn more about BIIB122 in participants with early-stage Parkinson's disease (PD). The study will include adults aged 30 to 80 who were diagnosed with PD within 2 years of starting the study.\n\nThe main objective of the study is to learn about the effect BIIB122 has on slowing down the worsening of PD symptoms. The main question researchers want to answer is:\n\n\\- How long does it take for PD symptoms to worsen during BIIB122 treatment?\n\nResearchers will answer this and other questions by measuring the symptoms of PD over time using a variety of scoring tools. These include the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the modified Schwab and England Activities of Daily Living Scale (mSE-ADL).\n\nThe MDS-UPDRS is used to measure symptoms of PD. It has 4 parts: Part I, II, III, and IV. Each part measures different aspects of motor and non-motor symptoms. The mSE-ADL measures a participant's ability to perform daily activities or personal chores.\n\nResearchers will also learn more about the safety of BIIB122. They will check participants for adverse events. Adverse events are unwanted health problems that may or may not be caused by the study drug.\n\nThe study will be done as follows:\n\n* Participants will be randomly assigned to take either BIIBB122 or placebo. A placebo looks like the study drug but contains no real medicine.\n* Neither the researchers nor the participants will know if the participants are receiving BIIB122 or placebo.\n* Participants will take BIIB122 or placebo tablets by mouth once a day.\n* The treatment period for each participant will last between 48 and 144 weeks.\n* There will be a safety follow-up period for 2 weeks after the last dose of BIIB122.\n* In total, participants will have up to 29 study visits.\n* Participants will stay in the study for at least 1 year, up to about 3 years.", "completionDate": "2026-03-09", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro", "hematology" ] }, "enrollmentCount": 650, "firstPostedDate": "2022-04-27", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122", "BIIB122-Matching Placebo" ], "nctId": "NCT05348785", "phase": "Phase 2", "primaryCompletionDate": "2026-02-25", "primaryPurpose": "TREATMENT", "startDate": "2022-04-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "BIIB122 is an investigational central nervous system-penetrant small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2). Participants who completed the early termination (ET) visit of the study 283PD302 (NCT05418673) would be eligible for screening of this study and if enrolled, these participants are not eligible for the sub studies of 283PD201.", "title": "A Study to Learn About the Safety of BIIB122 Tablets and Whether They Can Slow the Worsening of Early-Stage Parkinson's Disease in Adults Between the Ages of 30 and 80", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05348785", "whyStopped": "" } ] }, "clinvarEnrichment": null, "clinvarSummaryEnrichment": { "LRRK2": { "benignCount": 1811, "clinicalSignificanceRatio": 0, "gene": "LRRK2", "hasData": true, "likelyPathogenicCount": 9, "narrative": "LRRK2 ClinVar summary: 0 pathogenic, 9 likely-pathogenic, 2786 VUS, 1811 benign. P/LP ratio: 0%.", "pathogenicCount": 0, "source": "ClinVar", "totalCount": 4606, "vusCount": 2786 }, "PARK7": { "benignCount": 0, "clinicalSignificanceRatio": 100, "gene": "PARK7", "hasData": true, "likelyPathogenicCount": 0, "narrative": "PARK7 ClinVar summary: 66 pathogenic, 0 likely-pathogenic, 0 VUS, 0 benign. P/LP ratio: 100%.", "pathogenicCount": 66, "source": "ClinVar", "totalCount": 66, "vusCount": 0 } }, "combinationMatrix": [], "combinationSummary": { "highConfidencePairs": 0, "pairs": [], "topPair": null, "totalPairsAnalyzed": 0 }, "complexPortalEnrichment": null, "complexityAnalysis": { "audienceComplexity": 3, "biomedicalDepth": { "biomarker": 0, "clinical": 0, "molecular": 0, "pathway": 0, "pharmacology": 0 }, "biomedicalDepthScore": 0, "complexity": "simple", "complexityScore": 5.280000000000001, "contextComplexity": 1, "featureVector": { "audience": "researcher", "biomarkerDepth": 0, "biomedicalDepth": 4.65, "clinicalDepth": 0.2, "contextLength": 19, "geneCount": 3, "intent": "research", "intentScore": 0.46, "molecularDepth": 1, "pathwayDepth": 1, "pharmacologyDepth": 0.13 }, "geneCount": 3, "intent": { "confidence": 0.46, "label": "research", "multiplier": 1.1, "scores": { "clinical": 1, "diagnostic": 0, "drug_discovery": 0, "educational": 0, "research": 2 } }, "optimizationOpportunities": [], "optimizationStrategy": { "aiDepth": "focused", "caching": "aggressive", "dataSources": "essential", "description": "Fast analysis for simple queries", "literatureLimit": 8, "parallelism": "reduced", "pathwayLimit": 2, "skipSources": [ "dgidb", "pubchem" ], "timeout": 30000 }, "performancePrediction": { "basis": "prior", "confidenceLevel": 0.5, "lowerMs": 19250, "predictionMs": 27500, "sampleSize": 0, "upperMs": 37125 }, "performanceTarget": 25000, "riskAssessment": "medium", "timestamp": "2026-05-01T15:02:05.811Z" }, "contextNotes": { "trustConsistency": "Global grounding downgraded to match section-level sparse/speculative evidence.", "whatWouldConvinceMe": [ "Validate Alpha-synuclein aggregation and Lewy body formation activity in disease-relevant samples", "Assess feasibility of LRRK2 kinase inhibitors for SNCA and LRRK2 mutation carriers in preclinical models" ], "whereItMayFail": [ "Low evidence density; findings may be preliminary.", "Blood-brain barrier context may limit translation outside neuro settings." ], "whereThisHolds": [ "Scoped to Parkinson's disease and related literature.", "Cross-validated across 76 databases (30 returned data).", "Grounded evidence ratio is 36% across surfaced insights.", "Consensus signal: Strong.", "Context tags: BBB relevance, pH / temperature sensitivity, Immune context, Cell type: fibroblast, Cell type: neuron." ] }, "contextTags": [ "BBB relevance", "pH / temperature sensitivity", "Immune context", "Cell type: fibroblast", "Cell type: neuron" ], "cosmicSignatures": { "clinicalImplication": null, "diseaseKey": "default", "dominantSignatures": [ { "contrib": 42, "label": "Clock-like aging", "meta": { "color": "#64748b", "etiology": "Deamination of methylated cytosines — universal age-related process", "label": "Clock-like aging" }, "sig": "SBS1" }, { "contrib": 30, "label": "Clock-like", "meta": { "color": "#64748b", "etiology": "Clock-like signature, etiology unknown — ubiquitous in all cancers", "label": "Clock-like (unknown)" }, "sig": "SBS5" } ], "geneSigMap": {}, "genes": [ "LRRK2", "PARK7", "SNCA" ], "hasAPOBEC": false, "hasData": true, "hasMMRD": false, "hasPOLE": false, "hasSBS3_HRD": false, "narrative": "COSMIC mutational signatures (default): dominant process SBS1 — \"Clock-like aging\" (42% of mutations). ", "source": "COSMIC Mutational Signatures v3.4" }, "cptacEnrichment": { "PARK7": { "cohort": "CPTAC Parkinson Brain Proteome", "direction": "up", "diseaseMatched": true, "evidenceTier": "cohort_matched", "gene": "LRRK2", "narrative": "LRRK2 shows protein gain in CPTAC Parkinson Brain Proteome (protein z 1.3, phospho 1.8). ser1292 autophosphorylation elevated", "phosphoSignal": 1.8, "phosphoState": "ser1292 autophosphorylation elevated", "proteinAbundanceZ": 1.3, "signalStrength": 0.61, "significant": true, "source": "CPTAC (proteogenomics)", "topCohorts": [ { "cohort": "CPTAC Parkinson Brain Proteome", "matchedDisease": true, "phosphoSignal": 1.8, "proteinAbundanceZ": 1.3 } ] } }, "crossDiseaseEvidence": [], "crosstalkEnrichment": null, "dataAvailability": { "clinical": { "disgenet": true, "gwasCatalog": true, "openTargets": true, "pharmgkb": true }, "drugs": { "chembl": true, "clinicalTrials": true, "dgidb": true, "drugCentral": true, "drugbank": false, "openFDA": true, "pubchem": true }, "interactions": { "biogrid": true, "string": true }, "literature": { "pubmed": true, "semanticScholar": true }, "pathways": { "kegg": true, "reactome": true } }, "dataSource": { "ai": "DeepSeek V3", "clinical": "Open Targets + GWAS Catalog", "drugs": "DrugCentral + PubChem + DGIdb + Drug Target Commons + ChEMBL + Therapeutic Target Database + The ChEMBL Bioactivity Database", "genes": "Ensembl + ClinVar + UniProt + Gene Ontology", "interactions": "STRING", "internal": "SAE (ESM-2 + sparse autoencoder; 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Essential in 0% of lines (score ≤ -0.5). Classification: Non-essential / poor target. Most dependent tissues: adrenal gland (-0.016), testis (0.059), hepatopancreatic ampulla (0.089).", "source": "DepMap (Broad/OpenTargets)", "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.016, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": 0.059, "tissue": "testis" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": 0.089, "tissue": "hepatopancreatic ampulla" }, { "cellLineCount": 47, "essentialFraction": 0, "meanScore": 0.113, "tissue": "pancreas" }, { "cellLineCount": 63, "essentialFraction": 0, "meanScore": 0.117, "tissue": "intestine" }, { "cellLineCount": 59, "essentialFraction": 0, "meanScore": 0.121, "tissue": "internal female genitalia" } ], "totalCellLines": 1183 }, "PARK7": { "dataSource": "OpenTargets/DepMap", "essentialFraction": 0.004, "gene": "LRRK2", "isStrongTarget": false, "meanChronos": -0.147, "narrative": "LRRK2 DepMap Chronos score: mean -0.147 across 1183 cell lines. Essential in 0% of lines (score ≤ -0.5). Classification: Non-essential / poor target. Most dependent tissues: adrenal gland (-0.438), testis (-0.238), prostate gland (-0.208).", "source": "DepMap (Broad/OpenTargets)", "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.438, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": -0.238, "tissue": "testis" }, { "cellLineCount": 10, "essentialFraction": 0, "meanScore": -0.208, "tissue": "prostate gland" }, { "cellLineCount": 2, "essentialFraction": 0, "meanScore": -0.181, "tissue": "mammalian vulva" }, { "cellLineCount": 47, "essentialFraction": 0, "meanScore": -0.18, "tissue": "pancreas" }, { "cellLineCount": 45, "essentialFraction": 0, "meanScore": -0.175, "tissue": "Peripheral Nervous System" } ], "totalCellLines": 1183 }, "SNCA": { "dataSource": "OpenTargets/DepMap", "essentialFraction": 0.004, "gene": "PARK7", "isStrongTarget": false, "meanChronos": -0.149, "narrative": "PARK7 DepMap Chronos score: mean -0.149 across 1183 cell lines. 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It is converted from ANDROSTENEDIONE directly, or from TESTOSTERONE via ESTRADIOL. In humans, it is produced primarily by the cyclic ovaries, PLACENTA, and the ADIPOSE TISSUE of men and postmenopausal women.", "name": "estrone", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "1637", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A potent lipoxygenase inhibitor that interferes with arachidonic acid metabolism. The compound also inhibits formyltetrahydrofolate synthetase, carboxylesterase, and cyclooxygenase to a lesser extent. It also serves as an antioxidant in fats and oils.", "name": "masoprocol", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "1683", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "", "name": "menadione", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "1685", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "", "name": "menatetrenone", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2105", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A long-acting dopamine agonist which has been used to treat PARKINSON DISEASE and HYPERPROLACTINEMIA but withdrawn from some markets due to potential for HEART VALVE DISEASES.", "name": "pergolide", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "5597", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "", "name": "phenothiazine", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2843", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A lipid cofactor that is required for normal blood clotting. Several forms of vitamin K have been identified: VITAMIN K 1 (phytomenadione) derived from plants, VITAMIN K 2 (menaquinone) from bacteria, and synthetic naphthoquinone provitamins, VITAMIN K 3 (menadione). Vitamin K 3 provitamins, after being alkylated in vivo, exhibit the antifibrinolytic activity of vitamin K. Green leafy vegetables, liver, cheese, butter, and egg yolk are good sources of vitamin K.", "name": "phytomenadione", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "3514", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A flavonol widely distributed in plants. It is an antioxidant, like many other phenolic heterocyclic compounds. Glycosylated forms include RUTIN and quercetrin.", "name": "quercetin", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2831", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of CAROTENOIDS found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products.", "name": "retinol", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2372", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "", "name": "retinol acetate", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2377", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)", "name": "rifampicin", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2429", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A selective, irreversible inhibitor of Type B monoamine oxidase that is used for the treatment of newly diagnosed patients with PARKINSON DISEASE, and for the treatment of depressive disorders. The compound without isomeric designation is Deprenyl.", "name": "selegiline", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2607", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A potent androgenic steroid and major product secreted by the LEYDIG CELLS of the TESTIS. Its production is stimulated by LUTEINIZING HORMONE from the PITUITARY GLAND. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to DIHYDROTESTOSTERONE or ESTRADIOL.", "name": "testosterone", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "2611", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "A naphthacene antibiotic that inhibits AMINO ACYL TRNA binding during protein synthesis.", "name": "tetracycline", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "approved", "atcCode": "", "chemblId": null, "drugCentralId": "2722", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": true, "maxPhase": 4, "mechanismOfAction": "An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE).", "name": "tretinoin", "phaseLabel": "Approved", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" }, { "accession": null, "approvalStatus": "investigational", "atcCode": "", "chemblId": null, "drugCentralId": "4197", "genes": [ "SNCA" ], "indication": "", "interactionType": "mechanism_of_action", "isApproved": false, "maxPhase": 0, "mechanismOfAction": "", "name": "vitamin A palmitate", "phaseLabel": "Unknown", "pmids": [], "searchMethod": "target_card", "sourceCount": 1, "sources": [ "DrugCentral" ], "targets": [ "SNCA" ], "validated": "single-source" } ], "gene": "SNCA", "reason": null, "searchMethod": "target_card", "source": "DrugCentral", "status": "ok", "totalDrugs": 25, "uniprotId": "P37840" } }, "drugProviderHealth": { "chembl": { "attemptedGenes": 6, "available": true, "errorGenes": 0, "healthyGenes": 6, "provider": "ChEMBL", "status": "ok", "timeoutGenes": 0, "timeoutMs": 22000, "topReasons": [], "totalGenes": 3, "unavailableGenes": 0 }, "clinicalTrials": { "available": true, "provider": "ClinicalTrials.gov", "reason": null, "status": "ok", "trials": 3 }, "dgidb": { "attemptedGenes": 3, "available": true, "errorGenes": 0, "healthyGenes": 2, "provider": "DGIdb", "status": "ok", "timeoutGenes": 0, "timeoutMs": 20000, "totalGenes": 3, "unavailableGenes": 0 }, "drugCentral": { "attemptedGenes": 3, "available": true, "errorGenes": 0, "healthyGenes": 2, "provider": "DrugCentral", "status": "partial", "timeoutGenes": 0, "timeoutMs": 15000, "topReasons": [ "no_rows" ], "totalGenes": 3, "unavailableGenes": 1 }, "drugbank": { "attemptedGenes": 0, "available": false, "errorGenes": 0, "healthyGenes": 0, "provider": "DrugBank", "status": "disabled", "timeoutGenes": 0, "timeoutMs": null, "totalGenes": 3, "unavailableGenes": 0 }, "openFDA": { "available": true, "provider": "OpenFDA", "reason": null, "status": "ok" }, "pubchem": { "available": true, "compoundsEnriched": 19, "provider": "PubChem", "status": "ok" } }, "drugRepurposing": { "alphaFoldActive": true, "alphaFoldGeneCount": 3, "candidates": [ { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "admet": { "alogp": 2.97, "chemblId": "CHEMBL189963", "hba": 9, "hbd": 2, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "CDK6/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111455" }, { "action": "INHIBITOR", "description": "Cyclin-dependent kinase 4/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL1907601" } ], "moleculeType": "Small molecule", "mw": 447.54, "name": "PALBOCICLIB", "oralBio": "favorable", "psa": 105.04, "qed": 0.58, "ro5Violations": 0, "smiles": "CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "PALBOCICLIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "PALBOCICLIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": true, "biomarkerSignals": [ "erformance status", "menopausal status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA required biomarker stratification (erformance status, menopausal status); FDA approved 2019", "riskLevel": "moderate" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a 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"CHEMBL267" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase BRK inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4601" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase TIE-2 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4128" }, { "action": "INHIBITOR", "description": "Vascular endothelial growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2095227" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase receptor RET inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2041" }, { "action": "INHIBITOR", "description": "Ephrin receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363043" }, { "action": "INHIBITOR", "description": "Epidermal growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363049" } ], "moleculeType": "Small molecule", "mw": 475.36, "name": "VANDETANIB", "oralBio": "favorable", "psa": 62.74, "qed": 0.59, "ro5Violations": 0, "smiles": "COc1cc2/c(=N/c3ccc(Br)cc3F)nc[nH]c2cc1OCC1CCN(C)CC1", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "VANDETANIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "VANDETANIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "is high", "were high", "or high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2020", "riskLevel": "high" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "VANDETANIB acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of LRRK2", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "admet": { "alogp": 5.03, "chemblId": "CHEMBL1983268", "hba": 6, "hbd": 3, "isBiologic": false, "lipinskiPass": false, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Neurotrophic tyrosine kinase receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL3559684" }, { "action": "INHIBITOR", "description": "Proto-oncogene tyrosine-protein 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"matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ENTRECTINIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "ROS1- positive", "erformance status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": true, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Accelerated approval — confirmatory trial required; FDA approved 2023", "riskLevel": "low" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to 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"actionabilityScore": 0.43, "admet": { "alogp": 4.46, "chemblId": "CHEMBL64894", "hba": 2, "hbd": 0, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "DNA inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2364041" } ], "moleculeType": "Small molecule", "mw": 372.54, "name": "GENTIAN VIOLET", "oralBio": "favorable", "psa": 9.49, "qed": 0.73, "ro5Violations": 0, "smiles": "CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccc(N(C)C)cc2)cc1.[Cl-]", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "GENTIAN VIOLET CATION", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "GENTIAN VIOLET CATION is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": {}, "regulatorySummary": "No major regulatory flags identified", "riskLevel": "low" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "GENTIAN VIOLET CATION acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of SNCA", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "admet": { "alogp": 2.52, "chemblId": "CHEMBL1456", "hba": 8, "hbd": 1, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111369" } ], "moleculeType": "Small molecule", "mw": 433.5, "name": "MYCOPHENOLATE MOFETIL", "oralBio": "favorable", "psa": 94.53, "qed": 0.47, "ro5Violations": 0, "smiles": "COc1c(C)c2c(c(O)c1C/C=C(\\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "MYCOPHENOLATE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "MYCOPHENOLATE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "of negative", "of positive", "at high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2021", "riskLevel": "high" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "MYCOPHENOLATE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of SNCA", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "admet": { "alogp": 5.94, "chemblId": "CHEMBL1095057", "hba": 13, "hbd": 7, "isBiologic": false, "lipinskiPass": false, "maxPhase": null, "mechanisms": [], "moleculeType": "Small molecule", "mw": 822.01, "name": "DOXORUBICIN OLEYLHYDRAZONE HYDROCHLORIDE", "oralBio": "moderate/variable", "psa": 230.46, "qed": 0.02, "ro5Violations": 4, "smiles": "CCCCCCCC/C=C\\CCCCCCCC(=O)N/N=C(\\CO)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](O[C@H]2C[C@H](N)[C@H](O)[C@H](C)O2)C1)C(=O)c1c(OC)cccc1C3=O.Cl", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "DOXORUBICIN HYDROCHLORIDE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "DOXORUBICIN HYDROCHLORIDE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "with low", "nificantly high", "doses low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1997", "riskLevel": "high" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "DOXORUBICIN HYDROCHLORIDE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of SNCA", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "KETOCONAZOLE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "KETOCONAZOLE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA approved 2002", "riskLevel": "low" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "KETOCONAZOLE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of SNCA", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "tretinoin", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tretinoin is supported by DrugCentral with mechanism evidence: An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE)..", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "initiate high", "at low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1999", "riskLevel": "high" }, "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "tretinoin acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of SNCA", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "ruxolitinib", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ruxolitinib is supported by DrugCentral with mechanism evidence: a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Although some small studies have suggested possibility of benefit from ruxolitinib in patients with COVID-19, it is not recommended the use of JAK inhibitors other than baricitinib for the treatment of COVID-19..", "Mapped targets in panel: LRRK2." ], "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "ruxolitinib acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of LRRK2", "tier": "II", "tumorMatch": "unspecified" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.55, "mechanisticImportance": 0, "tractability": 0.95, "translationalFeasibility": 0.28 }, "actionabilityScore": 0.43, "canUseTargetsVerb": false, "claimEvidenceClass": "direct_functional_perturbation", "confidence": "medium", "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "directTargetEvidenceStrength": 0, "directness": "contextual", "drug": "tofacitinib", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "evidenceType": "indirect_modulation", "evidenceTypeLabel": "Indirect modulation", "fitScore": 50, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tofacitinib is supported by DrugCentral with mechanism evidence: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs..", "Mapped targets in panel: LRRK2." ], "relationType": "mechanistic_context", "repurposingScore": 50, "scoreLabel": "Provisional score (ranking capped)", "sourceClass": "literature_or_inference", "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "tofacitinib acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "targetRelationText": "indirect modulation of LRRK2", "tier": "II", "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "NEU-411", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "The goal of this Phase 2 clinical trial is to investigate the efficacy and safety of NEU-411 in men and women aged 40-80 years with early Parkinson's Disease (PD) who have predicted elevations in the activity of the \"leucine-rich repeat kinase 2\" (\"LRRK2\" for short) pathway based on their genetic profile. A DNA test will be used to identify the \"LRRK2-driven\" population with predicted elevation in the LRRK2 pathway.", "completionDate": "2027-09", "conditionSummary": "Parkinson Disease · Parkinson · Idiopathic Parkinson Disease", "conditions": [ "Parkinson Disease", "Parkinson", "Idiopathic Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 150, "firstPostedDate": "2024-11-08", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "NEU-411", "Placebo" ], "nctId": "NCT06680830", "phase": "Phase 2", "primaryCompletionDate": "2026-09", "primaryPurpose": "TREATMENT", "startDate": "2025-01-17", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "NEU-411-PD201 is a Phase 2, randomized, placebo-controlled, proof-of-concept study and open-label extension (OLE) in participants with early Parkinson's Disease (PD) who have LRRK2-driven PD as measured by an investigational companion diagnostic genetic test (CDx). The study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of NEU-411, an orally-administered, potent, selective, bioavailable, highly permeable, brain penetrant, small molecule inhibitor of LRRK2 activity as compared to placebo.\n\nAfter participants are screened for inclusion in the randomized, placebo-controlled portion of the study, approximately 150 participants will be randomized in a 1:1 allocation to NEU-411 30 mg once per day or placebo for a 52-week treatment period with a safety follow-up visit within 2 weeks after the last treatment visit. Eligible participants may enroll in the OLE and receive treatment for an additional 26 weeks.", "title": "A Phase 2 Study and Open-Label Extension of NEU-411 in Companion Diagnostic-Positive Participants With Early Parkinson's Disease", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06680830", "whyStopped": "" } ], "confidence": "medium", "contextRelevance": 60, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "Parkinson's disease", "drugName": "NEU-411", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 17, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 17, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Placebo", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "The goal of this Phase 2 clinical trial is to investigate the efficacy and safety of NEU-411 in men and women aged 40-80 years with early Parkinson's Disease (PD) who have predicted elevations in the activity of the \"leucine-rich repeat kinase 2\" (\"LRRK2\" for short) pathway based on their genetic profile. A DNA test will be used to identify the \"LRRK2-driven\" population with predicted elevation in the LRRK2 pathway.", "completionDate": "2027-09", "conditionSummary": "Parkinson Disease · Parkinson · Idiopathic Parkinson Disease", "conditions": [ "Parkinson Disease", "Parkinson", "Idiopathic Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 150, "firstPostedDate": "2024-11-08", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "NEU-411", "Placebo" ], "nctId": "NCT06680830", "phase": "Phase 2", "primaryCompletionDate": "2026-09", "primaryPurpose": "TREATMENT", "startDate": "2025-01-17", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "NEU-411-PD201 is a Phase 2, randomized, placebo-controlled, proof-of-concept study and open-label extension (OLE) in participants with early Parkinson's Disease (PD) who have LRRK2-driven PD as measured by an investigational companion diagnostic genetic test (CDx). The study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of NEU-411, an orally-administered, potent, selective, bioavailable, highly permeable, brain penetrant, small molecule inhibitor of LRRK2 activity as compared to placebo.\n\nAfter participants are screened for inclusion in the randomized, placebo-controlled portion of the study, approximately 150 participants will be randomized in a 1:1 allocation to NEU-411 30 mg once per day or placebo for a 52-week treatment period with a safety follow-up visit within 2 weeks after the last treatment visit. Eligible participants may enroll in the OLE and receive treatment for an additional 26 weeks.", "title": "A Phase 2 Study and Open-Label Extension of NEU-411 in Companion Diagnostic-Positive Participants With Early Parkinson's Disease", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06680830", "whyStopped": "" } ], "confidence": "medium", "contextRelevance": 60, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "Parkinson's disease", "drugName": "Placebo", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 17, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 17, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "BIIB122 225 mg", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "completionDate": "2028-02-28", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 50, "firstPostedDate": "2024-09-19", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122 225 mg", "BIIB122-Matching Placebo" ], "nctId": "NCT06602193", "phase": "Phase 2", "primaryCompletionDate": "2026-04-30", "primaryPurpose": "TREATMENT", "startDate": "2024-10-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "title": "Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06602193", "whyStopped": "" } ], "confidence": "medium", "contextRelevance": 60, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "Parkinson's disease", "drugName": "BIIB122 225 mg", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 17, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 17, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "BIIB122-Matching Placebo", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "completionDate": "2028-02-28", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 50, "firstPostedDate": "2024-09-19", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122 225 mg", "BIIB122-Matching Placebo" ], "nctId": "NCT06602193", "phase": "Phase 2", "primaryCompletionDate": "2026-04-30", "primaryPurpose": "TREATMENT", "startDate": "2024-10-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "title": "Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06602193", "whyStopped": "" } ], "confidence": "medium", "contextRelevance": 60, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "Parkinson's disease", "drugName": "BIIB122-Matching Placebo", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 17, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 17, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "BIIB122", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "In this study, researchers will learn more about BIIB122 in participants with early-stage Parkinson's disease (PD). The study will include adults aged 30 to 80 who were diagnosed with PD within 2 years of starting the study.\n\nThe main objective of the study is to learn about the effect BIIB122 has on slowing down the worsening of PD symptoms. The main question researchers want to answer is:\n\n\\- How long does it take for PD symptoms to worsen during BIIB122 treatment?\n\nResearchers will answer this and other questions by measuring the symptoms of PD over time using a variety of scoring tools. These include the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the modified Schwab and England Activities of Daily Living Scale (mSE-ADL).\n\nThe MDS-UPDRS is used to measure symptoms of PD. It has 4 parts: Part I, II, III, and IV. Each part measures different aspects of motor and non-motor symptoms. The mSE-ADL measures a participant's ability to perform daily activities or personal chores.\n\nResearchers will also learn more about the safety of BIIB122. They will check participants for adverse events. Adverse events are unwanted health problems that may or may not be caused by the study drug.\n\nThe study will be done as follows:\n\n* Participants will be randomly assigned to take either BIIBB122 or placebo. A placebo looks like the study drug but contains no real medicine.\n* Neither the researchers nor the participants will know if the participants are receiving BIIB122 or placebo.\n* Participants will take BIIB122 or placebo tablets by mouth once a day.\n* The treatment period for each participant will last between 48 and 144 weeks.\n* There will be a safety follow-up period for 2 weeks after the last dose of BIIB122.\n* In total, participants will have up to 29 study visits.\n* Participants will stay in the study for at least 1 year, up to about 3 years.", "completionDate": "2026-03-09", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro", "hematology" ] }, "enrollmentCount": 650, "firstPostedDate": "2022-04-27", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122", "BIIB122-Matching Placebo" ], "nctId": "NCT05348785", "phase": "Phase 2", "primaryCompletionDate": "2026-02-25", "primaryPurpose": "TREATMENT", "startDate": "2022-04-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "BIIB122 is an investigational central nervous system-penetrant small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2). Participants who completed the early termination (ET) visit of the study 283PD302 (NCT05418673) would be eligible for screening of this study and if enrolled, these participants are not eligible for the sub studies of 283PD201.", "title": "A Study to Learn About the Safety of BIIB122 Tablets and Whether They Can Slow the Worsening of Early-Stage Parkinson's Disease in Adults Between the Ages of 30 and 80", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05348785", "whyStopped": "" } ], "confidence": "medium", "contextRelevance": 60, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "Parkinson's disease", "drugName": "BIIB122", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 17, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 17, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro", "hematology" ] }, "tumorMatch": "unspecified" } ], "combinationMatrix": [], "combinationSummary": { "highConfidencePairs": 0, "pairs": [], "topPair": null, "totalPairsAnalyzed": 0 }, "combinations": [ { "drugA": "PALBOCICLIB", "drugB": "VANDETANIB", "rationale": "Computational combination hypothesis — requires experimental validation.", "synergyScore": 40 }, { "drugA": "PALBOCICLIB", "drugB": "ENTRECTINIB", "rationale": "Computational combination hypothesis — requires experimental validation.", "synergyScore": 40 }, { "drugA": "PALBOCICLIB", "drugB": "GENTIAN VIOLET CATION", "rationale": "Computational combination hypothesis — requires experimental validation.", "synergyScore": 40 } ], "enterpriseValue": "$10K-50K/year", "evidenceMode": "mechanism_first", "fallbackMode": "approved_drug_backfill", "hasMultipleSections": false, "hasMultipleTracks": false, "mechanismReviewLeads": [ { "_rankingCapApplied": "provisional", "drug": "PALBOCICLIB", "evidenceQualityFlag": "exploratory", "mechanism": "mechanism not characterized" }, { "_rankingCapApplied": "provisional", "drug": "VANDETANIB", "evidenceQualityFlag": "exploratory", "mechanism": "mechanism not characterized" }, { "_rankingCapApplied": "provisional", "drug": "ENTRECTINIB", "evidenceQualityFlag": "exploratory", "mechanism": "mechanism not characterized" }, { "_rankingCapApplied": "provisional", "drug": "GENTIAN VIOLET CATION", "evidenceQualityFlag": "exploratory", "mechanism": "mechanism not characterized" }, { "_rankingCapApplied": "provisional", "drug": "MYCOPHENOLATE", "evidenceQualityFlag": "exploratory", "mechanism": "mechanism not characterized" } ], "pathwayFdrStatus": { "anyFdrSignificant": false, "anyFdrSuggestive": false, "fdrSignificantCount": 0 }, "rankingCapApplied": "provisional", "stats": { "analysisTime": "39ms", "avgScore": 86, "candidatesFound": 10, "exploratoryCount": 0, "kinaseExpansionNote": "Panel virtually expanded with 12 upstream kinase regulators (RAB8A, RAB10, RILPL1, RILPL2…) to surface kinase inhibitors targeting substrate proteins", "kinaseExpansions": [ "RAB8A", "RAB10", "RILPL1", "RILPL2", "PPM1H", "GBA", "PINK1", "PRKN", "PLK2", "CK2", "GRK2", "GRK5" ], "minScore": 30, "onLabelContextCount": 0, "onlyApproved": false, "repurposingOpportunityCount": 0, "totalDrugsAnalyzed": 96 }, "summary": { "headline": "15 therapeutic candidates identified for Parkinson's disease", "recommendation": "Treat PALBOCICLIB as exploratory; validate indirect modulation of LRRK2 before target-level claims.", "summary": "Top therapeutic candidate: PALBOCICLIB (50% fit). Evidence: indirect modulation." }, "synergyPairs": [], "synergyPairsSuppressed": true, "synergyPairsSuppressedReason": "All compounds are exploratory — combination hypotheses suppressed", "targetRelationSummary": { "pathway_level_mechanism": [ "PALBOCICLIB", "VANDETANIB", "ENTRECTINIB", "GENTIAN VIOLET CATION", "MYCOPHENOLATE", "DOXORUBICIN HYDROCHLORIDE", "KETOCONAZOLE", "tretinoin", "ruxolitinib", "tofacitinib" ] }, "targetRelationViolations": 0, "therapeuticTracks": [ { "candidates": [ { "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.97, "chemblId": "CHEMBL189963", "hba": 9, "hbd": 2, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "CDK6/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111455" }, { "action": "INHIBITOR", "description": "Cyclin-dependent kinase 4/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL1907601" } ], "moleculeType": "Small molecule", "mw": 447.54, "name": "PALBOCICLIB", "oralBio": "favorable", "psa": 105.04, "qed": 0.58, "ro5Violations": 0, "smiles": "CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "PALBOCICLIB", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "PALBOCICLIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": true, "biomarkerSignals": [ "erformance status", "menopausal status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA required biomarker stratification (erformance status, menopausal status); FDA approved 2019", "riskLevel": "moderate" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "admet": { "alogp": 4.43, "chemblId": "CHEMBL24828", "hba": 5, "hbd": 1, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Tyrosine-protein kinase SRC inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL267" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase BRK inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4601" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase TIE-2 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4128" }, { "action": "INHIBITOR", "description": "Vascular endothelial growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2095227" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase receptor RET inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2041" }, { "action": "INHIBITOR", "description": "Ephrin receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363043" }, { "action": "INHIBITOR", "description": "Epidermal growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363049" } ], "moleculeType": "Small molecule", "mw": 475.36, "name": "VANDETANIB", "oralBio": "favorable", "psa": 62.74, "qed": 0.59, "ro5Violations": 0, "smiles": "COc1cc2/c(=N/c3ccc(Br)cc3F)nc[nH]c2cc1OCC1CCN(C)CC1", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "VANDETANIB", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "VANDETANIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "is high", "were high", "or high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2020", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "admet": { "alogp": 5.03, "chemblId": "CHEMBL1983268", "hba": 6, "hbd": 3, "isBiologic": false, "lipinskiPass": false, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Neurotrophic tyrosine kinase receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL3559684" }, { "action": "INHIBITOR", "description": "Proto-oncogene tyrosine-protein kinase ROS inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL5568" }, { "action": "INHIBITOR", "description": "ALK tyrosine kinase receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4247" } ], "moleculeType": "Small molecule", "mw": 560.65, "name": "ENTRECTINIB", "oralBio": "moderate/variable", "psa": 85.52, "qed": 0.29, "ro5Violations": 2, "smiles": "CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "ENTRECTINIB", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ENTRECTINIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "ROS1- positive", "erformance status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": true, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Accelerated approval — confirmatory trial required; FDA approved 2023", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "admet": { "alogp": 4.46, "chemblId": "CHEMBL64894", "hba": 2, "hbd": 0, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "DNA inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2364041" } ], "moleculeType": "Small molecule", "mw": 372.54, "name": "GENTIAN VIOLET", "oralBio": "favorable", "psa": 9.49, "qed": 0.73, "ro5Violations": 0, "smiles": "CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccc(N(C)C)cc2)cc1.[Cl-]", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "GENTIAN VIOLET CATION", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "GENTIAN VIOLET CATION is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": {}, "regulatorySummary": "No major regulatory flags identified", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.52, "chemblId": "CHEMBL1456", "hba": 8, "hbd": 1, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111369" } ], "moleculeType": "Small molecule", "mw": 433.5, "name": "MYCOPHENOLATE MOFETIL", "oralBio": "favorable", "psa": 94.53, "qed": 0.47, "ro5Violations": 0, "smiles": "COc1c(C)c2c(c(O)c1C/C=C(\\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "MYCOPHENOLATE", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "MYCOPHENOLATE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "of negative", "of positive", "at high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2021", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "admet": { "alogp": 5.94, "chemblId": "CHEMBL1095057", "hba": 13, "hbd": 7, "isBiologic": false, "lipinskiPass": false, "maxPhase": null, "mechanisms": [], "moleculeType": "Small molecule", "mw": 822.01, "name": "DOXORUBICIN OLEYLHYDRAZONE HYDROCHLORIDE", "oralBio": "moderate/variable", "psa": 230.46, "qed": 0.02, "ro5Violations": 4, "smiles": "CCCCCCCC/C=C\\CCCCCCCC(=O)N/N=C(\\CO)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](O[C@H]2C[C@H](N)[C@H](O)[C@H](C)O2)C1)C(=O)c1c(OC)cccc1C3=O.Cl", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "DOXORUBICIN HYDROCHLORIDE", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "DOXORUBICIN HYDROCHLORIDE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "with low", "nificantly high", "doses low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1997", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "KETOCONAZOLE", "evidenceQualityFlag": "exploratory", "fitScore": 87, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "KETOCONAZOLE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA approved 2002", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 87 }, { "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "tretinoin", "evidenceQualityFlag": "exploratory", "fitScore": 83, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tretinoin is supported by DrugCentral with mechanism evidence: An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE)..", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "initiate high", "at low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1999", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 83 }, { "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "ruxolitinib", "evidenceQualityFlag": "exploratory", "fitScore": 83, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ruxolitinib is supported by DrugCentral with mechanism evidence: a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Although some small studies have suggested possibility of benefit from ruxolitinib in patients with COVID-19, it is not recommended the use of JAK inhibitors other than baricitinib for the treatment of COVID-19..", "Mapped targets in panel: LRRK2." ], "relationType": "exploratory_inference", "repurposingScore": 83 }, { "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "tofacitinib", "evidenceQualityFlag": "exploratory", "fitScore": 83, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tofacitinib is supported by DrugCentral with mechanism evidence: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs..", "Mapped targets in panel: LRRK2." ], "relationType": "exploratory_inference", "repurposingScore": 83 } ], "topCandidate": { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.97, "chemblId": "CHEMBL189963", "hba": 9, "hbd": 2, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "CDK6/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111455" }, { "action": "INHIBITOR", "description": "Cyclin-dependent kinase 4/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL1907601" } ], "moleculeType": "Small molecule", "mw": 447.54, "name": "PALBOCICLIB", "oralBio": "favorable", "psa": 105.04, "qed": 0.58, "ro5Violations": 0, "smiles": "CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "PALBOCICLIB", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "PALBOCICLIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": true, "biomarkerSignals": [ "erformance status", "menopausal status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA required biomarker stratification (erformance status, menopausal status); FDA approved 2019", "riskLevel": "moderate" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "tier": "II" }, "trackId": "unclassified", "trackLabel": "Broad Mechanistic Targeting" } ], "therapyEvidenceSections": [ { "candidates": [ { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.97, "chemblId": "CHEMBL189963", "hba": 9, "hbd": 2, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "CDK6/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111455" }, { "action": "INHIBITOR", "description": "Cyclin-dependent kinase 4/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL1907601" } ], "moleculeType": "Small molecule", "mw": 447.54, "name": "PALBOCICLIB", "oralBio": "favorable", "psa": 105.04, "qed": 0.58, "ro5Violations": 0, "smiles": "CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "PALBOCICLIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "PALBOCICLIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": true, "biomarkerSignals": [ "erformance status", "menopausal status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA required biomarker stratification (erformance status, menopausal status); FDA approved 2019", "riskLevel": "moderate" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "PALBOCICLIB acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 4.43, "chemblId": "CHEMBL24828", "hba": 5, "hbd": 1, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Tyrosine-protein kinase SRC inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL267" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase BRK inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4601" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase TIE-2 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4128" }, { "action": "INHIBITOR", "description": "Vascular endothelial growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2095227" }, { "action": "INHIBITOR", "description": "Tyrosine-protein kinase receptor RET inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2041" }, { "action": "INHIBITOR", "description": "Ephrin receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363043" }, { "action": "INHIBITOR", "description": "Epidermal growth factor receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2363049" } ], "moleculeType": "Small molecule", "mw": 475.36, "name": "VANDETANIB", "oralBio": "favorable", "psa": 62.74, "qed": 0.59, "ro5Violations": 0, "smiles": "COc1cc2/c(=N/c3ccc(Br)cc3F)nc[nH]c2cc1OCC1CCN(C)CC1", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "VANDETANIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "VANDETANIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "is high", "were high", "or high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2020", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "VANDETANIB acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 5.03, "chemblId": "CHEMBL1983268", "hba": 6, "hbd": 3, "isBiologic": false, "lipinskiPass": false, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Neurotrophic tyrosine kinase receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL3559684" }, { "action": "INHIBITOR", "description": "Proto-oncogene tyrosine-protein kinase ROS inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL5568" }, { "action": "INHIBITOR", "description": "ALK tyrosine kinase receptor inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL4247" } ], "moleculeType": "Small molecule", "mw": 560.65, "name": "ENTRECTINIB", "oralBio": "moderate/variable", "psa": 85.52, "qed": 0.29, "ro5Violations": 2, "smiles": "CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "ENTRECTINIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ENTRECTINIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "ROS1- positive", "erformance status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": true, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Accelerated approval — confirmatory trial required; FDA approved 2023", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "ENTRECTINIB acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 4.46, "chemblId": "CHEMBL64894", "hba": 2, "hbd": 0, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "DNA inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2364041" } ], "moleculeType": "Small molecule", "mw": 372.54, "name": "GENTIAN VIOLET", "oralBio": "favorable", "psa": 9.49, "qed": 0.73, "ro5Violations": 0, "smiles": "CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccc(N(C)C)cc2)cc1.[Cl-]", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "GENTIAN VIOLET CATION", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "GENTIAN VIOLET CATION is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": {}, "regulatorySummary": "No major regulatory flags identified", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "GENTIAN VIOLET CATION acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.52, "chemblId": "CHEMBL1456", "hba": 8, "hbd": 1, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "Inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111369" } ], "moleculeType": "Small molecule", "mw": 433.5, "name": "MYCOPHENOLATE MOFETIL", "oralBio": "favorable", "psa": 94.53, "qed": 0.47, "ro5Violations": 0, "smiles": "COc1c(C)c2c(c(O)c1C/C=C(\\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "MYCOPHENOLATE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "MYCOPHENOLATE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "of negative", "of positive", "at high" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 2021", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "MYCOPHENOLATE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 5.94, "chemblId": "CHEMBL1095057", "hba": 13, "hbd": 7, "isBiologic": false, "lipinskiPass": false, "maxPhase": null, "mechanisms": [], "moleculeType": "Small molecule", "mw": 822.01, "name": "DOXORUBICIN OLEYLHYDRAZONE HYDROCHLORIDE", "oralBio": "moderate/variable", "psa": 230.46, "qed": 0.02, "ro5Violations": 4, "smiles": "CCCCCCCC/C=C\\CCCCCCCC(=O)N/N=C(\\CO)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](O[C@H]2C[C@H](N)[C@H](O)[C@H](C)O2)C1)C(=O)c1c(OC)cccc1C3=O.Cl", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "DOXORUBICIN HYDROCHLORIDE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "DOXORUBICIN HYDROCHLORIDE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "with low", "nificantly high", "doses low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1997", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "DOXORUBICIN HYDROCHLORIDE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "KETOCONAZOLE", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "KETOCONAZOLE is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA approved 2002", "riskLevel": "low" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "KETOCONAZOLE acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "tretinoin", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "SNCA" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tretinoin is supported by DrugCentral with mechanism evidence: An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE)..", "Mapped targets in panel: SNCA." ], "regulatoryIntel": { "biomarkerRequired": false, "biomarkerSignals": [ "initiate high", "at low" ], "hasBlackBox": true, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "Black-box warning present; FDA approved 1999", "riskLevel": "high" }, "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "tretinoin acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "ruxolitinib", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "ruxolitinib is supported by DrugCentral with mechanism evidence: a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Although some small studies have suggested possibility of benefit from ruxolitinib in patients with COVID-19, it is not recommended the use of JAK inhibitors other than baricitinib for the treatment of COVID-19..", "Mapped targets in panel: LRRK2." ], "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "ruxolitinib acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" }, { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "tofacitinib", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "tofacitinib is supported by DrugCentral with mechanism evidence: Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs..", "Mapped targets in panel: LRRK2." ], "relationType": "exploratory_inference", "repurposingScore": 69, "scoreLabel": "Provisional score (ranking capped)", "targetRelation": "pathway_level_mechanism", "targetRelationExplanation": { "evidenceClass": "pathway_context_target", "evidenceClassLabel": "Pathway-Context Therapy", "panelRelation": "pathway_upstream_downstream", "sectionRationale": "Drug targets a pathway node related to the panel but has no confirmed direct binding to a panel gene product.", "targetingSummary": "tofacitinib acts on a pathway node relevant to this panel but does not directly bind a panel gene.", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Pathway-Level Mechanism", "tier": "II" } ], "sectionDescription": "Drugs targeting pathway nodes upstream or downstream of panel genes — therapeutically relevant but not direct binders.", "sectionId": "pathway_context_target", "sectionLabel": "Pathway-Context Therapy", "topCandidate": { "_rankingCapApplied": "provisional", "_therapeuticTrack": "unclassified", "admet": { "alogp": 2.97, "chemblId": "CHEMBL189963", "hba": 9, "hbd": 2, "isBiologic": false, "lipinskiPass": true, "maxPhase": "4.0", "mechanisms": [ { "action": "INHIBITOR", "description": "CDK6/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL2111455" }, { "action": "INHIBITOR", "description": "Cyclin-dependent kinase 4/cyclin D1 inhibitor", "direct": 1, "diseaseEfficacy": 1, "target": "CHEMBL1907601" } ], "moleculeType": "Small molecule", "mw": 447.54, "name": "PALBOCICLIB", "oralBio": "favorable", "psa": 105.04, "qed": 0.58, "ro5Violations": 0, "smiles": "CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O", "source": "ChEMBL v34" }, "canUseTargetsVerb": false, "confidence": "medium", "currentIndication": "Existing approved indication", "directBindingMatchedTargets": [], "drug": "PALBOCICLIB", "enforcedTier": "II", "evidenceQualityFlag": "exploratory", "fitScore": 69, "matchedTargets": [ "LRRK2" ], "otDivergent": false, "otValidated": false, "phase": "FDA Approved", "positioning": "repurposing_opportunity", "primaryEvidenceClass": "pathway_context_target", "proposedIndication": "Parkinson's disease", "readinessScore": 8, "reasoning": [ "PALBOCICLIB is supported by DGIdb with mechanism evidence: Unknown.", "Mapped targets in panel: LRRK2." ], "regulatoryIntel": { "biomarkerRequired": true, "biomarkerSignals": [ "erformance status", "menopausal status" ], "hasBlackBox": false, "regulatoryPathway": { "acceleratedApproval": false, "breakthroughTherapy": false, "fastTrack": false, "priorityReview": false, "rtor": false }, "regulatorySummary": "FDA required biomarker stratification (erformance status, menopausal status); 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Franconi F, Frankel LB, Friedman SL, Fröhlich LF, Frühbeck G, Fuentes JM, Fujiki Y, Fujita N, Fujiwara Y, Fukuda M, Fulda S, Furic L, Furuya N, Fusco C, Gack MU, Gaffke L, Galadari S, Galasso A, Galindo MF, Gallolu Kankanamalage S, Galluzzi L, Galy V, Gammoh N, Gan B, Ganley IG, Gao F, Gao H, Gao M, Gao P, Gao SJ, Gao W, Gao X, Garcera A, Garcia MN, Garcia VE, García-Del Portillo F, Garcia-Escudero V, Garcia-Garcia A, Garcia-Macia M, García-Moreno D, Garcia-Ruiz C, García-Sanz P, Garg AD, Gargini R, Garofalo T, Garry RF, Gassen NC, Gatica D, Ge L, Ge W, Geiss-Friedlander R, Gelfi C, Genschik P, Gentle IE, Gerbino V, Gerhardt C, Germain K, Germain M, Gewirtz DA, Ghasemipour Afshar E, Ghavami S, Ghigo A, Ghosh M, Giamas G, Giampietri C, Giatromanolaki A, Gibson GE, Gibson SB, Ginet V, Giniger E, Giorgi C, Girao H, Girardin SE, Giridharan M, Giuliano S, Giulivi C, Giuriato S, Giustiniani J, Gluschko A, Goder V, Goginashvili A, Golab J, Goldstone DC, Golebiewska A, Gomes LR, Gomez R, Gómez-Sánchez R, Gomez-Puerto MC, Gomez-Sintes R, Gong Q, Goni FM, González-Gallego J, Gonzalez-Hernandez T, Gonzalez-Polo RA, Gonzalez-Reyes JA, González-Rodríguez P, Goping IS, Gorbatyuk MS, Gorbunov NV, Görgülü K, Gorojod RM, Gorski SM, Goruppi S, Gotor C, Gottlieb RA, Gozes I, Gozuacik D, Graef M, Gräler MH, Granatiero V, Grasso D, Gray JP, Green DR, Greenhough A, Gregory SL, Griffin EF, Grinstaff MW, Gros F, Grose C, Gross AS, Gruber F, Grumati P, Grune T, Gu X, Guan JL, Guardia CM, Guda K, Guerra F, Guerri C, Guha P, Guillén C, Gujar S, Gukovskaya A, Gukovsky I, Gunst J, Günther A, Guntur AR, Guo C, Guo C, Guo H, Guo LW, Guo M, Gupta P, Gupta SK, Gupta S, Gupta VB, Gupta V, Gustafsson AB, Gutterman DD, H B R, Haapasalo A, Haber JE, Hać A, Hadano S, Hafrén AJ, Haidar M, Hall BS, Halldén G, Hamacher-Brady A, Hamann A, Hamasaki M, Han W, Hansen M, Hanson PI, Hao Z, Harada M, Harhaji-Trajkovic L, Hariharan N, Haroon N, Harris J, Hasegawa T, Hasima Nagoor N, Haspel JA, Haucke V, Hawkins WD, Hay BA, Haynes CM, Hayrabedyan SB, Hays TS, He C, He Q, He RR, He YW, He YY, Heakal Y, Heberle AM, Hejtmancik JF, Helgason GV, Henkel V, Herb M, Hergovich A, Herman-Antosiewicz A, Hernández A, Hernandez C, Hernandez-Diaz S, Hernandez-Gea V, Herpin A, Herreros J, Hervás JH, Hesselson D, Hetz C, Heussler VT, Higuchi Y, Hilfiker S, Hill JA, Hlavacek WS, Ho EA, Ho IHT, Ho PW, Ho SL, Ho WY, Hobbs GA, Hochstrasser M, Hoet PHM, Hofius D, Hofman P, Höhn A, Holmberg CI, Hombrebueno JR, Yi-Ren Hong CH, Hooper LV, Hoppe T, Horos R, Hoshida Y, Hsin IL, Hsu HY, Hu B, Hu D, Hu LF, Hu MC, Hu R, Hu W, Hu YC, Hu ZW, Hua F, Hua J, Hua Y, Huan C, Huang C, Huang C, Huang C, Huang C, Huang H, Huang K, Huang MLH, Huang R, Huang S, Huang T, Huang X, Huang YJ, Huber TB, Hubert V, Hubner CA, Hughes SM, Hughes WE, Humbert M, Hummer G, Hurley JH, Hussain S, Hussain S, Hussey PJ, Hutabarat M, Hwang HY, Hwang S, Ieni A, Ikeda F, Imagawa Y, Imai Y, Imbriano C, Imoto M, Inman DM, Inoki K, Iovanna J, Iozzo RV, Ippolito G, Irazoqui JE, Iribarren P, Ishaq M, Ishikawa M, Ishimwe N, Isidoro C, Ismail N, Issazadeh-Navikas S, Itakura E, Ito D, Ivankovic D, Ivanova S, Iyer AKV, Izquierdo JM, Izumi M, Jäättelä M, Jabir MS, Jackson WT, Jacobo-Herrera N, Jacomin AC, Jacquin E, Jadiya P, Jaeschke H, Jagannath C, Jakobi AJ, Jakobsson J, Janji B, Jansen-Dürr P, Jansson PJ, Jantsch J, Januszewski S, Jassey A, Jean S, Jeltsch-David H, Jendelova P, Jenny A, Jensen TE, Jessen N, Jewell JL, Ji J, Jia L, Jia R, Jiang L, Jiang Q, Jiang R, Jiang T, Jiang X, Jiang Y, Jimenez-Sanchez M, Jin EJ, Jin F, Jin H, Jin L, Jin L, Jin M, Jin S, Jo EK, Joffre C, Johansen T, Johnson GVW, Johnston SA, Jokitalo E, Jolly MK, Joosten LAB, Jordan J, Joseph B, Ju D, Ju JS, Ju J, Juárez E, Judith D, Juhász G, Jun Y, Jung CH, Jung SC, Jung YK, Jungbluth H, Jungverdorben J, Just S, Kaarniranta K, Kaasik A, Kabuta T, Kaganovich D, Kahana A, Kain R, Kajimura S, Kalamvoki M, Kalia M, Kalinowski DS, Kaludercic N, Kalvari I, Kaminska J, Kaminskyy VO, Kanamori H, Kanasaki K, Kang C, Kang R, Kang SS, Kaniyappan S, Kanki T, Kanneganti TD, Kanthasamy AG, Kanthasamy A, Kantorow M, Kapuy O, Karamouzis MV, Karim MR, Karmakar P, Katare RG, Kato M, Kaufmann SHE, Kauppinen A, Kaushal GP, Kaushik S, Kawasaki K, Kazan K, Ke PY, Keating DJ, Keber U, Kehrl JH, Keller KE, Keller CW, Kemper JK, Kenific CM, Kepp O, Kermorgant S, Kern A, Ketteler R, Keulers TG, Khalfin B, Khalil H, Khambu B, Khan SY, Khandelwal VKM, Khandia R, Kho W, Khobrekar NV, Khuansuwan S, Khundadze M, Killackey SA, Kim D, Kim DR, Kim DH, Kim DE, Kim EY, Kim EK, Kim HR, Kim HS, Hyung-Ryong Kim, Kim JH, Kim JK, Kim JH, Kim J, Kim JH, Kim KI, Kim PK, Kim SJ, Kimball SR, Kimchi A, Kimmelman AC, Kimura T, King MA, Kinghorn KJ, Kinsey CG, Kirkin V, Kirshenbaum LA, Kiselev SL, Kishi S, Kitamoto K, Kitaoka Y, Kitazato K, Kitsis RN, Kittler JT, Kjaerulff O, Klein PS, Klopstock T, Klucken J, Knævelsrud H, Knorr RL, Ko BCB, Ko F, Ko JL, Kobayashi H, Kobayashi S, Koch I, Koch JC, Koenig U, Kögel D, Koh YH, Koike M, Kohlwein SD, Kocaturk NM, Komatsu M, König J, Kono T, Kopp BT, Korcsmaros T, Korkmaz G, Korolchuk VI, Korsnes MS, Koskela A, Kota J, Kotake Y, Kotler ML, Kou Y, Koukourakis MI, Koustas E, Kovacs AL, Kovács T, Koya D, Kozako T, Kraft C, Krainc D, Krämer H, Krasnodembskaya AD, Kretz-Remy C, Kroemer G, Ktistakis NT, Kuchitsu K, Kuenen S, Kuerschner L, Kukar T, Kumar A, Kumar A, Kumar D, Kumar D, Kumar S, Kume S, Kumsta C, Kundu CN, Kundu M, Kunnumakkara AB, Kurgan L, Kutateladze TG, Kutlu O, Kwak S, Kwon HJ, Kwon TK, Kwon YT, Kyrmizi I, La Spada A, Labonté P, Ladoire S, Laface I, Lafont F, Lagace DC, Lahiri V, Lai Z, Laird AS, Laird AS, Lakkaraju A, Lamark T, Lan SH, Landajuela A, Lane DJR, Lane JD, Lang CH, Lange C, Langel Ü, Langer R, Lapaquette P, Laporte J, LaRusso NF, Lastres-Becker I, Lau WCY, Laurie GW, Lavandero S, Law BYK, Law HK, Layfield R, Le W, Le Stunff H, Leary AY, Lebrun JJ, Leck LYW, Leduc-Gaudet JP, Lee C, Lee CP, Lee DH, Lee EB, Lee EF, Lee GM, Lee HJ, Lee HK, Lee JM, Lee JS, Lee JA, Lee JY, Lee JH, Lee M, Lee MG, Lee MJ, Lee MS, Lee SY, Lee SJ, Lee SY, Lee SB, Lee WH, Lee YR, Lee YH, Lee Y, Lefebvre C, Legouis R, Lei YL, Lei Y, Leikin S, Leitinger G, Lemus L, Leng S, Lenoir O, Lenz G, Lenz HJ, Lenzi P, León Y, Leopoldino AM, Leschczyk C, Leskelä S, Letellier E, Leung CT, Leung PS, Leventhal JS, Levine B, Lewis PA, Ley K, Li B, Li DQ, Li J, Li J, Li J, Li K, Li L, Li M, Li M, Li M, Li M, Li M, Li PL, Li MQ, Li Q, Li S, Li T, Li W, Li W, Li X, Li YP, Li Y, Li Z, Li Z, Li Z, Lian J, Liang C, Liang Q, Liang W, Liang Y, Liang Y, Liao G, Liao L, Liao M, Liao YF, Librizzi M, Lie PPY, Lilly MA, Lim HJ, Lima TRR, Limana F, Lin C, Lin CW, Lin DS, Lin FC, Lin JD, Lin KM, Lin KH, Lin LT, Lin PH, Lin Q, Lin S, Lin SJ, Lin W, Lin X, Lin YX, Lin YS, Linden R, Lindner P, Ling SC, Lingor P, Linnemann AK, Liou YC, Lipinski MM, Lipovšek S, Lira VA, Lisiak N, Liton PB, Liu C, Liu CH, Liu CF, Liu CH, Liu F, Liu H, Liu HS, Liu HF, Liu H, Liu J, Liu J, Liu J, Liu L, Liu L, Liu M, Liu Q, Liu W, Liu W, Liu XH, Liu X, Liu X, Liu X, Liu X, Liu Y, Liu Y, Liu Y, Liu Y, Liu Y, Livingston JA, Lizard G, Lizcano JM, Ljubojevic-Holzer S, LLeonart ME, Llobet-Navàs D, Llorente A, Lo CH, Lobato-Márquez D, Long Q, Long YC, Loos B, Loos JA, López MG, López-Doménech G, López-Guerrero JA, López-Jiménez AT, López-Pérez Ó, López-Valero I, Lorenowicz MJ, Lorente M, Lorincz P, Lossi L, Lotersztajn S, Lovat PE, Lovell JF, Lovy A, Lőw P, Lu G, Lu H, Lu JH, Lu JJ, Lu M, Lu S, Luciani A, Lucocq JM, Ludovico P, Luftig MA, Luhr M, Luis-Ravelo D, Lum JJ, Luna-Dulcey L, Lund AH, Lund VK, Lünemann JD, Lüningschrör P, Luo H, Luo R, Luo S, Luo Z, Luparello C, Lüscher B, Luu L, Lyakhovich A, Lyamzaev KG, Lystad AH, Lytvynchuk L, Ma AC, Ma C, Ma M, Ma NF, Ma QH, Ma X, Ma Y, Ma Z, MacDougald OA, Macian F, MacIntosh GC, MacKeigan JP, Macleod KF, Maday S, Madeo F, Madesh M, Madl T, Madrigal-Matute J, Maeda A, Maejima Y, Magarinos M, Mahavadi P, Maiani E, Maiese K, Maiti P, Maiuri MC, Majello B, Major MB, Makareeva E, Malik F, Mallilankaraman K, Malorni W, Maloyan A, Mammadova N, Man GCW, Manai F, Mancias JD, Mandelkow EM, Mandell MA, Manfredi AA, Manjili MH, Manjithaya R, Manque P, Manshian BB, Manzano R, Manzoni C, Mao K, Marchese C, Marchetti S, Marconi AM, Marcucci F, Mardente S, Mareninova OA, Margeta M, Mari M, Marinelli S, Marinelli O, Mariño G, Mariotto S, Marshall RS, Marten MR, Martens S, Martin APJ, Martin KR, Martin S, Martin S, Martín-Segura A, Martín-Acebes MA, Martin-Burriel I, Martin-Rincon M, Martin-Sanz P, Martina JA, Martinet W, Martinez A, Martinez A, Martinez J, Martinez Velazquez M, Martinez-Lopez N, Martinez-Vicente M, Martins DO, Martins JO, Martins WK, Martins-Marques T, Marzetti E, Masaldan S, Masclaux-Daubresse C, Mashek DG, Massa V, Massieu L, Masson GR, Masuelli L, Masyuk AI, Masyuk TV, Matarrese P, Matheu A, Matoba S, Matsuzaki S, Mattar P, Matte A, Mattoscio D, Mauriz JL, Mauthe M, Mauvezin C, Maverakis E, Maycotte P, Mayer J, Mazzoccoli G, Mazzoni C, Mazzulli JR, McCarty N, McDonald C, McGill MR, McKenna SL, McLaughlin B, McLoughlin F, McNiven MA, McWilliams TG, Mechta-Grigoriou F, Medeiros TC, Medina DL, Megeney LA, Megyeri K, Mehrpour M, Mehta JL, Meijer AJ, Meijer AH, Mejlvang J, Meléndez A, Melk A, Memisoglu G, Mendes AF, Meng D, Meng F, Meng T, Menna-Barreto R, Menon MB, Mercer C, Mercier AE, Mergny JL, Merighi A, Merkley SD, Merla G, Meske V, Mestre AC, Metur SP, Meyer C, Meyer H, Mi W, Mialet-Perez J, Miao J, Micale L, Miki Y, Milan E, Milczarek M, Miller DL, Miller SI, Miller S, Millward SW, Milosevic I, Minina EA, Mirzaei H, Mirzaei HR, Mirzaei M, Mishra A, Mishra N, Mishra PK, Misirkic Marjanovic M, Misasi R, Misra A, Misso G, Mitchell C, Mitou G, Miura T, Miyamoto S, Miyazaki M, Miyazaki M, Miyazaki T, Miyazawa K, Mizushima N, Mogensen TH, Mograbi B, Mohammadinejad R, Mohamud Y, Mohanty A, Mohapatra S, Möhlmann T, Mohmmed A, Moles A, Moley KH, Molinari M, Mollace V, Møller AB, Mollereau B, Mollinedo F, Montagna C, Monteiro MJ, Montella A, Montes LR, Montico B, Mony VK, Monzio Compagnoni G, Moore MN, Moosavi MA, Mora AL, Mora M, Morales-Alamo D, Moratalla R, Moreira PI, Morelli E, Moreno S, Moreno-Blas D, Moresi V, Morga B, Morgan AH, Morin F, Morishita H, Moritz OL, Moriyama M, Moriyasu Y, Morleo M, Morselli E, Moruno-Manchon JF, Moscat J, Mostowy S, Motori E, Moura AF, Moustaid-Moussa N, Mrakovcic M, Muciño-Hernández G, Mukherjee A, Mukhopadhyay S, Mulcahy Levy JM, Mulero V, Muller S, Münch C, Munjal A, Munoz-Canoves P, Muñoz-Galdeano T, Münz C, Murakawa T, Muratori C, Murphy BM, Murphy JP, Murthy A, Myöhänen TT, Mysorekar IU, Mytych J, Nabavi SM, Nabissi M, Nagy P, Nah J, Nahimana A, Nakagawa I, Nakamura K, Nakatogawa H, Nandi SS, Nanjundan M, Nanni M, Napolitano G, Nardacci R, Narita M, Nassif M, Nathan I, Natsumeda M, Naude RJ, Naumann C, Naveiras O, Navid F, Nawrocki ST, Nazarko TY, Nazio F, Negoita F, Neill T, Neisch AL, Neri LM, Netea MG, Neubert P, Neufeld TP, Neumann D, Neutzner A, Newton PT, Ney PA, Nezis IP, Ng CCW, Ng TB, Nguyen HTT, Nguyen LT, Ni HM, Ní Cheallaigh C, Ni Z, Nicolao MC, Nicoli F, Nieto-Diaz M, Nilsson P, Ning S, Niranjan R, Nishimune H, Niso-Santano M, Nixon RA, Nobili A, Nobrega C, Noda T, Nogueira-Recalde U, Nolan TM, Nombela I, Novak I, Novoa B, Nozawa T, Nukina N, Nussbaum-Krammer C, Nylandsted J, O'Donovan TR, O'Leary SM, O'Rourke EJ, O'Sullivan MP, O'Sullivan TE, Oddo S, Oehme I, Ogawa M, Ogier-Denis E, Ogmundsdottir MH, Ogretmen B, Oh GT, Oh SH, Oh YJ, Ohama T, Ohashi Y, Ohmuraya M, Oikonomou V, Ojha R, Okamoto K, Okazawa H, Oku M, Oliván S, Oliveira JMA, Ollmann M, Olzmann JA, Omari S, Omary MB, Önal G, Ondrej M, Ong SB, Ong SG, Onnis A, Orellana JA, Orellana JA, Orellana-Muñoz S, Ortega-Villaizan MDM, Ortiz-Gonzalez XR, Ortona E, Osiewacz HD, Osman AK, Osta R, Otegui MS, Otsu K, Ott C, Ottobrini L, Ou JJ, Outeiro TF, Oynebraten I, Ozturk M, Pagès G, Pahari S, Pajares M, Pajvani UB, Pal R, Paladino S, Pallet N, Palmieri M, Palmisano G, Palumbo C, Pampaloni F, Pan L, Pan Q, Pan W, Pan X, Panasyuk G, Pandey R, Pandey UB, Pandya V, Paneni F, Pang SY, Panzarini E, Papademetrio DL, Papaleo E, Papinski D, Papp D, Park EC, Park HT, Park JM, Park JI, Park JT, Park J, Park SC, Park SY, Parola AH, Parys JB, Pasquier A, Pasquier B, Passos JF, Pastore N, Patel HH, Patschan D, Pattingre S, Pedraza-Alva G, Pedraza-Chaverri J, Pedrozo Z, Pei G, Pei J, Peled-Zehavi H, Pellegrini JM, Pelletier J, Peñalva MA, Peng D, Peng Y, Penna F, Pennuto M, Pentimalli F, Pereira CM, Pereira GJS, Pereira LC, Pereira de Almeida L, Perera ND, Pérez-Lara Á, Perez-Oliva AB, Pérez-Pérez ME, Periyasamy P, Perl A, Perrotta C, Perrotta I, Pestell RG, Petersen M, Petrache I, Petrovski G, Pfirrmann T, Pfister AS, Philips JA, Pi H, Picca A, Pickrell AM, Picot S, Pierantoni GM, Pierdominici M, Pierre P, Pierrefite-Carle V, Pierzynowska K, Pietrocola F, Pietruczuk M, Pignata C, Pimentel-Muiños FX, Pinar M, Pinheiro RO, Pinkas-Kramarski R, Pinton P, Pircs K, Piya S, Pizzo P, Plantinga TS, Platta HW, Plaza-Zabala A, Plomann M, Plotnikov EY, Plun-Favreau H, Pluta R, Pocock R, Pöggeler S, Pohl C, Poirot M, Poletti A, Ponpuak M, Popelka H, Popova B, Porta H, Porte Alcon S, Portilla-Fernandez E, Post M, Potts MB, Poulton J, Powers T, Prahlad V, Prajsnar TK, Praticò D, Prencipe R, Priault M, Proikas-Cezanne T, Promponas VJ, Proud CG, Puertollano R, Puglielli L, Pulinilkunnil T, Puri D, Puri R, Puyal J, Qi X, Qi Y, Qian W, Qiang L, Qiu Y, Quadrilatero J, Quarleri J, Raben N, Rabinowich H, Ragona D, Ragusa MJ, Rahimi N, Rahmati M, Raia V, Raimundo N, Rajasekaran NS, Ramachandra Rao S, Rami A, Ramírez-Pardo I, Ramsden DB, Randow F, Rangarajan PN, Ranieri D, Rao H, Rao L, Rao R, Rathore S, Ratnayaka JA, Ratovitski EA, Ravanan P, Ravegnini G, Ray SK, Razani B, Rebecca V, Reggiori F, Régnier-Vigouroux A, Reichert AS, Reigada D, Reiling JH, Rein T, Reipert S, Rekha RS, Ren H, Ren J, Ren W, Renault T, Renga G, Reue K, Rewitz K, Ribeiro de Andrade Ramos B, Riazuddin SA, Ribeiro-Rodrigues TM, Ricci JE, Ricci R, Riccio V, Richardson DR, Rikihisa Y, Risbud MV, Risueño RM, Ritis K, Rizza S, Rizzuto R, Roberts HC, Roberts LD, Robinson KJ, Roccheri MC, Rocchi S, Rodney GG, Rodrigues T, Rodrigues Silva VR, Rodriguez A, Rodriguez-Barrueco R, Rodriguez-Henche N, Rodriguez-Rocha H, Roelofs J, Rogers RS, Rogov VV, Rojo AI, Rolka K, Romanello V, Romani L, Romano A, Romano PS, Romeo-Guitart D, Romero LC, Romero M, Roney JC, Rongo C, Roperto S, Rosenfeldt MT, Rosenstiel P, Rosenwald AG, Roth KA, Roth L, Roth S, Rouschop KMA, Roussel BD, Roux S, Rovere-Querini P, Roy A, Rozieres A, Ruano D, Rubinsztein DC, Rubtsova MP, Ruckdeschel K, Ruckenstuhl C, Rudolf E, Rudolf R, Ruggieri A, Ruparelia AA, Rusmini P, Russell RR, Russo GL, Russo M, Russo R, Ryabaya OO, Ryan KM, Ryu KY, Sabater-Arcis M, Sachdev U, Sacher M, Sachse C, Sadhu A, Sadoshima J, Safren N, Saftig P, Sagona AP, Sahay G, Sahebkar A, Sahin M, Sahin O, Sahni S, Saito N, Saito S, Saito T, Sakai R, Sakai Y, Sakamaki JI, Saksela K, Salazar G, Salazar-Degracia A, Salekdeh GH, Saluja AK, Sampaio-Marques B, Sanchez MC, Sanchez-Alcazar JA, Sanchez-Vera V, Sancho-Shimizu V, Sanderson JT, Sandri M, Santaguida S, Santambrogio L, Santana MM, Santoni G, Sanz A, Sanz P, Saran S, Sardiello M, Sargeant TJ, Sarin A, Sarkar C, Sarkar S, Sarrias MR, Sarkar S, Sarmah DT, Sarparanta J, Sathyanarayan A, Sathyanarayanan R, Scaglione KM, Scatozza F, Schaefer L, Schafer ZT, Schaible UE, Schapira AHV, Scharl M, Schatzl HM, Schein CH, Scheper W, Scheuring D, Schiaffino MV, Schiappacassi M, Schindl R, Schlattner U, Schmidt O, Schmitt R, Schmidt SD, Schmitz I, Schmukler E, Schneider A, Schneider BE, Schober R, Schoijet AC, Schott MB, Schramm M, Schröder B, Schuh K, Schüller C, Schulze RJ, Schürmanns L, Schwamborn JC, Schwarten M, Scialo F, Sciarretta S, Scott MJ, Scotto KW, Scovassi AI, Scrima A, Scrivo A, Sebastian D, Sebti S, Sedej S, Segatori L, Segev N, Seglen PO, Seiliez I, Seki E, Selleck SB, Sellke FW, Selsby JT, Sendtner M, Senturk S, Seranova E, Sergi C, Serra-Moreno R, Sesaki H, Settembre C, Setty SRG, Sgarbi G, Sha O, Shacka JJ, Shah JA, Shang D, Shao C, Shao F, Sharbati S, Sharkey LM, Sharma D, Sharma G, Sharma K, Sharma P, Sharma S, Shen HM, Shen H, Shen J, Shen M, Shen W, Shen Z, Sheng R, Sheng Z, Sheng ZH, Shi J, Shi X, Shi YH, Shiba-Fukushima K, Shieh JJ, Shimada Y, Shimizu S, Shimozawa M, Shintani T, Shoemaker CJ, Shojaei S, Shoji I, Shravage BV, Shridhar V, Shu CW, Shu HB, Shui K, Shukla AK, Shutt TE, Sica V, Siddiqui A, Sierra A, Sierra-Torre V, Signorelli S, Sil P, Silva BJA, Silva JD, Silva-Pavez E, Silvente-Poirot S, Simmonds RE, Simon AK, Simon HU, Simons M, Singh A, Singh LP, Singh R, Singh SV, Singh SK, Singh SB, Singh S, Singh SP, Sinha D, Sinha RA, Sinha S, Sirko A, Sirohi K, Sivridis EL, Skendros P, Skirycz A, Slaninová I, Smaili SS, Smertenko A, Smith MD, Soenen SJ, Sohn EJ, Sok SPM, Solaini G, Soldati T, Soleimanpour SA, Soler RM, Solovchenko A, Somarelli JA, Sonawane A, Song F, Song HK, Song JX, Song K, Song Z, Soria LR, Sorice M, Soukas AA, Soukup SF, Sousa D, Sousa N, Spagnuolo PA, Spector SA, Srinivas Bharath MM, St Clair D, Stagni V, Staiano L, Stalnecker CA, Stankov MV, Stathopulos PB, Stefan K, Stefan SM, Stefanis L, Steffan JS, Steinkasserer A, Stenmark H, Sterneckert J, Stevens C, Stoka V, Storch S, Stork B, Strappazzon F, Strohecker AM, Stupack DG, Su H, Su LY, Su L, Suarez-Fontes AM, Subauste CS, Subbian S, Subirada PV, Sudhandiran G, Sue CM, Sui X, Summers C, Sun G, Sun J, Sun K, Sun MX, Sun Q, Sun Y, Sun Z, Sunahara KKS, Sundberg E, Susztak K, Sutovsky P, Suzuki H, Sweeney G, Symons JD, Sze SCW, Szewczyk NJ, Tabęcka-Łonczynska A, Tabolacci C, Tacke F, Taegtmeyer H, Tafani M, Tagaya M, Tai H, Tait SWG, Takahashi Y, Takats S, Talwar P, Tam C, Tam SY, Tampellini D, Tamura A, Tan CT, Tan EK, Tan YQ, Tanaka M, Tanaka M, Tang D, Tang J, Tang TS, Tanida I, Tao Z, Taouis M, Tatenhorst L, Tavernarakis N, Taylor A, Taylor GA, Taylor JM, Tchetina E, Tee AR, Tegeder I, Teis D, Teixeira N, Teixeira-Clerc F, Tekirdag KA, Tencomnao T, Tenreiro S, Tepikin AV, Testillano PS, Tettamanti G, Tharaux PL, Thedieck K, Thekkinghat AA, Thellung S, Thinwa JW, Thirumalaikumar VP, Thomas SM, Thomes PG, Thorburn A, Thukral L, Thum T, Thumm M, Tian L, Tichy A, Till A, Timmerman V, Titorenko VI, Todi SV, Todorova K, Toivonen JM, Tomaipitinca L, Tomar D, Tomas-Zapico C, Tomić S, Tong BC, Tong C, Tong X, Tooze SA, Torgersen ML, Torii S, Torres-López L, Torriglia A, Towers CG, Towns R, Toyokuni S, Trajkovic V, Tramontano D, Tran QG, Travassos LH, Trelford CB, Tremel S, Trougakos IP, Tsao BP, Tschan MP, Tse HF, Tse TF, Tsugawa H, Tsvetkov AS, Tumbarello DA, Tumtas Y, Tuñón MJ, Turcotte S, Turk B, Turk V, Turner BJ, Tuxworth RI, Tyler JK, Tyutereva EV, Uchiyama Y, Ugun-Klusek A, Uhlig HH, Ułamek-Kozioł M, Ulasov IV, Umekawa M, Ungermann C, Unno R, Urbe S, 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SY, Wu S, Wu WKK, Wu X, Wu X, Wu YW, Wu Y, Xavier RJ, Xia H, Xia L, Xia Z, Xiang G, Xiang J, Xiang M, Xiang W, Xiao B, Xiao G, Xiao H, Xiao HT, Xiao J, Xiao L, Xiao S, Xiao Y, Xie B, Xie CM, Xie M, Xie Y, Xie Z, Xie Z, Xilouri M, Xu C, Xu E, Xu H, Xu J, Xu J, Xu L, Xu WW, Xu X, Xue Y, Yakhine-Diop SMS, Yamaguchi M, Yamaguchi O, Yamamoto A, Yamashina S, Yan S, Yan SJ, Yan Z, Yanagi Y, Yang C, Yang DS, Yang H, Yang HT, Yang H, Yang JM, Yang J, Yang J, Yang L, Yang L, Yang M, Yang PM, Yang Q, Yang S, Yang S, Yang SF, Yang W, Yang WY, Yang X, Yang X, Yang Y, Yang Y, Yao H, Yao S, Yao X, Yao YG, Yao YM, Yasui T, Yazdankhah M, Yen PM, Yi C, Yin XM, Yin Y, Yin Z, Yin Z, Ying M, Ying Z, Yip CK, Yiu SPT, Yoo YH, Yoshida K, Yoshii SR, Yoshimori T, Yousefi B, Yu B, Yu H, Yu J, Yu J, Yu L, Yu ML, Yu SW, Yu VC, Yu WH, Yu Z, Yu Z, Yuan J, Yuan LQ, Yuan S, Yuan SF, Yuan Y, Yuan Z, Yue J, Yue Z, Yun J, Yung RL, Zacks DN, Zaffagnini G, Zambelli VO, Zanella I, Zang QS, Zanivan S, Zappavigna S, Zaragoza P, Zarbalis KS, Zarebkohan A, Zarrouk A, Zeitlin SO, Zeng J, Zeng JD, Žerovnik E, Zhan L, Zhang B, Zhang DD, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang H, Zhang HL, Zhang J, Zhang J, Zhang JP, Zhang KYB, Zhang LW, Zhang L, Zhang L, Zhang L, Zhang L, Zhang M, Zhang P, Zhang S, Zhang W, Zhang X, Zhang XW, Zhang X, Zhang X, Zhang X, Zhang X, Zhang XD, Zhang Y, Zhang Y, Zhang Y, Zhang YD, Zhang Y, Zhang YY, Zhang Y, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhang Z, Zhao H, Zhao L, Zhao S, Zhao T, Zhao XF, Zhao Y, Zhao Y, Zhao Y, Zhao Y, Zheng G, Zheng K, Zheng L, Zheng S, Zheng XL, Zheng Y, Zheng ZG, Zhivotovsky B, Zhong Q, Zhou A, Zhou B, Zhou C, Zhou G, Zhou H, Zhou H, Zhou H, Zhou J, Zhou J, Zhou J, Zhou J, Zhou K, Zhou R, Zhou XJ, Zhou Y, Zhou Y, Zhou Y, Zhou ZY, Zhou Z, Zhu B, Zhu C, Zhu GQ, Zhu H, Zhu H, Zhu H, Zhu WG, Zhu Y, Zhu Y, Zhuang H, Zhuang X, Zientara-Rytter K, Zimmermann CM, Ziviani E, Zoladek T, Zong WX, Zorov DB, Zorzano A, Zou W, Zou Z, Zou Z, Zuryn S, Zwerschke W, Brand-Saberi B, Dong XC, Kenchappa CS, Li Z, Lin Y, Oshima S, Rong Y, Sluimer JC, Stallings CL, Tong CK.", "citedByCount": 2088, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Lysosomes", "Animals", "Humans", "Biological Assay", "Autophagy" ], "pmcid": "PMC7996087", "pmid": "33634751", "title": "Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)<sup>1</sup>.", "year": "2021" }, { "abstractText": "

Background

Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkins", "authorString": "Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A, Bras J, Young E, von Coelln R, Simón-Sánchez J, Schulte C, Sharma M, Krohn L, Pihlstrøm L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs JR, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, Sutherland M, Tienari P, Majamaa K, Toft M, Andreassen OA, Bangale T, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood NW, Hinds DA, Hardy JA, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB, 23andMe Research Team, System Genomics of Parkinson's Disease Consortium, International Parkinson's Disease Genomics Consortium.", "citedByCount": 2036, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Humans", "Parkinson Disease", "Genetic Predisposition to Disease", "Risk Factors", "Databases, Genetic" ], "pmcid": "PMC8422160", "pmid": "31701892", "title": "Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.", "year": "2019" }, { "abstractText": "Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a", "authorString": "Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM, Bitton A, Dassopoulos T, Datta LW, Green T, Griffiths AM, Kistner EO, Murtha MT, Regueiro MD, Rotter JI, Schumm LP, Steinhart AH, Targan SR, Xavier RJ, NIDDK IBD Genetics Consortium, Libioulle C, Sandor C, Lathrop M, Belaiche J, Dewit O, Gut I, Heath S, Laukens D, Mni M, Rutgeerts P, Van Gossum A, Zelenika D, Franchimont D, Hugot JP, de Vos M, Vermeire S, Louis E, Belgian-French IBD Consortium, Wellcome Trust Case Control Consortium, Cardon LR, Anderson CA, Drummond H, Nimmo E, Ahmad T, Prescott NJ, Onnie CM, Fisher SA, Marchini J, Ghori J, Bumpstead S, Gwilliam R, Tremelling M, Deloukas P, Mansfield J, Jewell D, Satsangi J, Mathew CG, Parkes M, Georges M, Daly MJ.", "citedByCount": 2025, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Humans", "Crohn Disease", "Genetic Predisposition to Disease", "Quantitative Trait Loci", "Genome, Human" ], "pmcid": "PMC2574810", "pmid": "18587394", "title": "Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.", "year": "2008" }, { "abstractText": "Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body i", "authorString": "Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Martí Carrera I, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB.", "citedByCount": 1870, "hasFullText": false, "isOpenAccess": false, "meshTerms": [ "Animals", "Humans", "Parkinson Disease", "Protein Kinases", "Nerve Tissue Proteins" ], "pmid": "15541308", "title": "Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.", "year": "2004" } ], "source": "Europe PMC", "topCitedCount": 2280, "totalFound": 9827 }, "PARK7": { "gene": "PARK7", "hasData": true, "narrative": "PARK7 Europe PMC: 3,467 papers. Top: \"Autophagy and the integrated stress response.\" (2729 cit., 2010). 1/6 open-access.", "openAccessCount": 1, "papers": [ { "abstractText": "Autophagy is a tightly regulated pathway involving the lysosomal degradation of cytoplasmic organelles or cytosolic components. This pathway can be stimulated by multiple forms of cellular stress, including nutrient or growth factor deprivation, hypoxia, reactive oxygen species, DNA damage, protein ", "authorString": "Kroemer G, Mariño G, Levine B.", "citedByCount": 2729, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Lysosomes", "Animals", "Humans", "Signal Transduction", "Apoptosis" ], "pmcid": "PMC3127250", "pmid": "20965422", "title": "Autophagy and the integrated stress response.", "year": "2010" }, { "abstractText": "Inflammation is associated with many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neuronal dysfun", "authorString": "Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH.", "citedByCount": 2654, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Brain", "Animals", "Humans", "Neurodegenerative Diseases", "Inflammation" ], "pmcid": "PMC2873093", "pmid": "20303880", "title": "Mechanisms underlying inflammation in neurodegeneration.", "year": "2010" }, { "abstractText": "In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formula", "authorString": "Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar PV, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gómez E, Alessandri C, Ali M, Alim Al-Bari MA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Álvarez ÉMC, Alves S, Alves da Costa C, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Antón Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araújo WL, Araya J, Arden C, Arévalo MA, 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Der CJ, Deretic V, Descoteaux A, Devis L, Devkota S, Devuyst O, Dewson G, Dharmasivam M, Dhiman R, di Bernardo D, Di Cristina M, Di Domenico F, Di Fazio P, Di Fonzo A, Di Guardo G, Di Guglielmo GM, Di Leo L, Di Malta C, Di Nardo A, Di Rienzo M, Di Sano F, Diallinas G, Diao J, Diaz-Araya G, Díaz-Laviada I, Dickinson JM, Diederich M, Dieudé M, Dikic I, Ding S, Ding WX, Dini L, Dinić J, Dinic M, Dinkova-Kostova AT, Dionne MS, Distler JHW, Diwan A, Dixon IMC, Djavaheri-Mergny M, Dobrinski I, Dobrovinskaya O, Dobrowolski R, Dobson RCJ, Đokić J, Dokmeci Emre S, Donadelli M, Dong B, Dong X, Dong Z, Dorn Ii GW, Dotsch V, Dou H, Dou J, Dowaidar M, Dridi S, Drucker L, Du A, Du C, Du G, Du HN, Du LL, du Toit A, Duan SB, Duan X, Duarte SP, Dubrovska A, Dunlop EA, Dupont N, Durán RV, Dwarakanath BS, Dyshlovoy SA, Ebrahimi-Fakhari D, Eckhart L, Edelstein CL, Efferth T, Eftekharpour E, Eichinger L, Eid N, Eisenberg T, Eissa NT, Eissa S, Ejarque M, El Andaloussi A, El-Hage N, El-Naggar S, Eleuteri AM, El-Shafey ES, Elgendy M, Eliopoulos AG, Elizalde MM, Elks PM, Elsasser HP, Elsherbiny ES, Emerling BM, Emre NCT, Eng CH, Engedal N, Engelbrecht AM, Engelsen AST, Enserink JM, Escalante R, Esclatine A, Escobar-Henriques M, Eskelinen EL, Espert L, Eusebio MO, Fabrias G, Fabrizi C, Facchiano A, Facchiano F, Fadeel B, Fader C, Faesen AC, Fairlie WD, Falcó A, Falkenburger BH, Fan D, Fan J, Fan Y, Fang EF, Fang Y, Fang Y, Fanto M, Farfel-Becker T, Faure M, Fazeli G, Fedele AO, Feldman AM, Feng D, Feng J, Feng L, Feng Y, Feng Y, Feng W, Fenz Araujo T, Ferguson TA, Fernández ÁF, Fernandez-Checa JC, Fernández-Veledo S, Fernie AR, Ferrante AW, Ferraresi A, Ferrari MF, Ferreira JCB, Ferro-Novick S, Figueras A, Filadi R, Filigheddu N, Filippi-Chiela E, Filomeni G, Fimia GM, Fineschi V, Finetti F, Finkbeiner S, Fisher EA, Fisher PB, Flamigni F, Fliesler SJ, Flo TH, Florance I, Florey O, Florio T, Fodor E, Follo C, Fon EA, Forlino A, Fornai F, Fortini P, Fracassi A, Fraldi A, Franco B, Franco R, Franconi F, Frankel LB, Friedman SL, Fröhlich LF, Frühbeck G, Fuentes JM, Fujiki Y, Fujita N, Fujiwara Y, Fukuda M, Fulda S, Furic L, Furuya N, Fusco C, Gack MU, Gaffke L, Galadari S, Galasso A, Galindo MF, Gallolu Kankanamalage S, Galluzzi L, Galy V, Gammoh N, Gan B, Ganley IG, Gao F, Gao H, Gao M, Gao P, Gao SJ, Gao W, Gao X, Garcera A, Garcia MN, Garcia VE, García-Del Portillo F, Garcia-Escudero V, Garcia-Garcia A, Garcia-Macia M, García-Moreno D, Garcia-Ruiz C, García-Sanz P, Garg AD, Gargini R, Garofalo T, Garry RF, Gassen NC, Gatica D, Ge L, Ge W, Geiss-Friedlander R, Gelfi C, Genschik P, Gentle IE, Gerbino V, Gerhardt C, Germain K, Germain M, Gewirtz DA, Ghasemipour Afshar E, Ghavami S, Ghigo A, Ghosh M, Giamas G, Giampietri C, Giatromanolaki A, Gibson GE, Gibson SB, Ginet V, Giniger E, Giorgi C, Girao H, Girardin SE, Giridharan M, Giuliano S, Giulivi C, Giuriato S, Giustiniani J, Gluschko A, Goder V, Goginashvili A, Golab J, Goldstone DC, Golebiewska A, Gomes LR, Gomez R, Gómez-Sánchez R, Gomez-Puerto MC, Gomez-Sintes R, Gong Q, Goni FM, González-Gallego J, Gonzalez-Hernandez T, Gonzalez-Polo RA, Gonzalez-Reyes JA, González-Rodríguez P, Goping IS, Gorbatyuk MS, Gorbunov NV, Görgülü K, Gorojod RM, Gorski SM, Goruppi S, Gotor C, Gottlieb RA, Gozes I, Gozuacik D, Graef M, Gräler MH, Granatiero V, Grasso D, Gray JP, Green DR, Greenhough A, Gregory SL, Griffin EF, Grinstaff MW, Gros F, Grose C, Gross AS, Gruber F, Grumati P, Grune T, Gu X, Guan JL, Guardia CM, Guda K, Guerra F, Guerri C, Guha P, Guillén C, Gujar S, Gukovskaya A, Gukovsky I, Gunst J, Günther A, Guntur AR, Guo C, Guo C, Guo H, Guo LW, Guo M, Gupta P, Gupta SK, Gupta S, Gupta VB, Gupta V, Gustafsson AB, Gutterman DD, H B R, Haapasalo A, Haber JE, Hać A, Hadano S, Hafrén AJ, Haidar M, Hall BS, Halldén G, Hamacher-Brady A, Hamann A, Hamasaki M, Han W, Hansen M, Hanson PI, Hao Z, Harada M, Harhaji-Trajkovic L, Hariharan N, Haroon N, Harris J, Hasegawa T, Hasima Nagoor N, Haspel JA, Haucke V, Hawkins WD, Hay BA, Haynes CM, Hayrabedyan SB, Hays TS, He C, He Q, He RR, He YW, He YY, Heakal Y, Heberle AM, Hejtmancik JF, Helgason GV, Henkel V, Herb M, Hergovich A, Herman-Antosiewicz A, Hernández A, Hernandez C, Hernandez-Diaz S, Hernandez-Gea V, Herpin A, Herreros J, Hervás JH, Hesselson D, Hetz C, Heussler VT, Higuchi Y, Hilfiker S, Hill JA, Hlavacek WS, Ho EA, Ho IHT, Ho PW, Ho SL, Ho WY, Hobbs GA, Hochstrasser M, Hoet PHM, Hofius D, Hofman P, Höhn A, Holmberg CI, Hombrebueno JR, Yi-Ren Hong CH, Hooper LV, Hoppe T, Horos R, Hoshida Y, Hsin IL, Hsu HY, Hu B, Hu D, Hu LF, Hu MC, Hu R, Hu W, Hu YC, Hu ZW, Hua F, Hua J, Hua Y, Huan C, Huang C, Huang C, Huang C, Huang C, Huang H, Huang K, Huang MLH, Huang R, Huang S, Huang T, Huang X, Huang YJ, Huber TB, Hubert V, Hubner CA, Hughes SM, Hughes WE, Humbert M, Hummer G, Hurley JH, Hussain S, Hussain S, Hussey PJ, Hutabarat M, Hwang HY, Hwang S, Ieni A, Ikeda F, Imagawa Y, Imai Y, Imbriano C, Imoto M, Inman DM, Inoki K, Iovanna J, Iozzo RV, Ippolito G, Irazoqui JE, Iribarren P, Ishaq M, Ishikawa M, Ishimwe N, Isidoro C, Ismail N, Issazadeh-Navikas S, Itakura E, Ito D, Ivankovic D, Ivanova S, Iyer AKV, Izquierdo JM, Izumi M, Jäättelä M, Jabir MS, Jackson WT, Jacobo-Herrera N, Jacomin AC, Jacquin E, Jadiya P, Jaeschke H, Jagannath C, Jakobi AJ, Jakobsson J, Janji B, Jansen-Dürr P, Jansson PJ, Jantsch J, Januszewski S, Jassey A, Jean S, Jeltsch-David H, Jendelova P, Jenny A, Jensen TE, Jessen N, Jewell JL, Ji J, Jia L, Jia R, Jiang L, Jiang Q, Jiang R, Jiang T, Jiang X, Jiang Y, Jimenez-Sanchez M, Jin EJ, Jin F, Jin H, Jin L, Jin L, Jin M, Jin S, Jo EK, Joffre C, Johansen T, Johnson GVW, Johnston SA, Jokitalo E, Jolly MK, Joosten LAB, Jordan J, Joseph B, Ju D, Ju JS, Ju J, Juárez E, Judith D, Juhász G, Jun Y, Jung CH, Jung SC, Jung YK, Jungbluth H, Jungverdorben J, Just S, Kaarniranta K, Kaasik A, Kabuta T, Kaganovich D, Kahana A, Kain R, Kajimura S, Kalamvoki M, Kalia M, Kalinowski DS, Kaludercic N, Kalvari I, Kaminska J, Kaminskyy VO, Kanamori H, Kanasaki K, Kang C, Kang R, Kang SS, Kaniyappan S, Kanki T, Kanneganti TD, Kanthasamy AG, Kanthasamy A, Kantorow M, Kapuy O, Karamouzis MV, Karim MR, Karmakar P, Katare RG, Kato M, Kaufmann SHE, Kauppinen A, Kaushal GP, Kaushik S, Kawasaki K, Kazan K, Ke PY, Keating DJ, Keber U, Kehrl JH, Keller KE, Keller CW, Kemper JK, Kenific CM, Kepp O, Kermorgant S, Kern A, Ketteler R, Keulers TG, Khalfin B, Khalil H, Khambu B, Khan SY, Khandelwal VKM, Khandia R, Kho W, Khobrekar NV, Khuansuwan S, Khundadze M, Killackey SA, Kim D, Kim DR, Kim DH, Kim DE, Kim EY, Kim EK, Kim HR, Kim HS, Hyung-Ryong Kim, Kim JH, Kim JK, Kim JH, Kim J, Kim JH, Kim KI, Kim PK, Kim SJ, Kimball SR, Kimchi A, Kimmelman AC, Kimura T, King MA, Kinghorn KJ, Kinsey CG, Kirkin V, Kirshenbaum LA, Kiselev SL, Kishi S, Kitamoto K, Kitaoka Y, Kitazato K, Kitsis RN, Kittler JT, Kjaerulff O, Klein PS, Klopstock T, Klucken J, Knævelsrud H, Knorr RL, Ko BCB, Ko F, Ko JL, Kobayashi H, Kobayashi S, Koch I, Koch JC, Koenig U, Kögel D, Koh YH, Koike M, Kohlwein SD, Kocaturk NM, Komatsu M, König J, Kono T, Kopp BT, Korcsmaros T, Korkmaz G, Korolchuk VI, Korsnes MS, Koskela A, Kota J, Kotake Y, Kotler ML, Kou Y, Koukourakis MI, Koustas E, Kovacs AL, Kovács T, Koya D, Kozako T, Kraft C, Krainc D, Krämer H, Krasnodembskaya AD, Kretz-Remy C, Kroemer G, Ktistakis NT, Kuchitsu K, Kuenen S, Kuerschner L, Kukar T, Kumar A, Kumar A, Kumar D, Kumar D, Kumar S, Kume S, Kumsta C, Kundu CN, Kundu M, Kunnumakkara AB, Kurgan L, Kutateladze TG, Kutlu O, Kwak S, Kwon HJ, Kwon TK, Kwon YT, Kyrmizi I, La Spada A, Labonté P, Ladoire S, Laface I, Lafont F, Lagace DC, Lahiri V, Lai Z, Laird AS, Laird AS, Lakkaraju A, Lamark T, Lan SH, Landajuela A, Lane DJR, Lane JD, Lang CH, Lange C, Langel Ü, Langer R, Lapaquette P, Laporte J, LaRusso NF, Lastres-Becker I, Lau WCY, Laurie GW, Lavandero S, Law BYK, Law HK, Layfield R, Le W, Le Stunff H, Leary AY, Lebrun JJ, Leck LYW, Leduc-Gaudet JP, Lee C, Lee CP, Lee DH, Lee EB, Lee EF, Lee GM, Lee HJ, Lee HK, Lee JM, Lee JS, Lee JA, Lee JY, Lee JH, Lee M, Lee MG, Lee MJ, Lee MS, Lee SY, Lee SJ, Lee SY, Lee SB, Lee WH, Lee YR, Lee YH, Lee Y, Lefebvre C, Legouis R, Lei YL, Lei Y, Leikin S, Leitinger G, Lemus L, Leng S, Lenoir O, Lenz G, Lenz HJ, Lenzi P, León Y, Leopoldino AM, Leschczyk C, Leskelä S, Letellier E, Leung CT, Leung PS, Leventhal JS, Levine B, Lewis PA, Ley K, Li B, Li DQ, Li J, Li J, Li J, Li K, Li L, Li M, Li M, Li M, Li M, Li M, Li PL, Li MQ, Li Q, Li S, Li T, Li W, Li W, Li X, Li YP, Li Y, Li Z, Li Z, Li Z, Lian J, Liang C, Liang Q, Liang W, Liang Y, Liang Y, Liao G, Liao L, Liao M, Liao YF, Librizzi M, Lie PPY, Lilly MA, Lim HJ, Lima TRR, Limana F, Lin C, Lin CW, Lin DS, Lin FC, Lin JD, Lin KM, Lin KH, Lin LT, Lin PH, Lin Q, Lin S, Lin SJ, Lin W, Lin X, Lin YX, Lin YS, Linden R, Lindner P, Ling SC, Lingor P, Linnemann AK, Liou YC, Lipinski MM, Lipovšek S, Lira VA, Lisiak N, Liton PB, Liu C, Liu CH, Liu CF, Liu CH, Liu F, Liu H, Liu HS, Liu HF, Liu H, Liu J, Liu J, Liu J, Liu L, Liu L, Liu M, Liu Q, Liu W, Liu W, Liu XH, Liu X, Liu X, Liu X, Liu X, Liu Y, Liu Y, Liu Y, Liu Y, Liu Y, Livingston JA, Lizard G, Lizcano JM, Ljubojevic-Holzer S, LLeonart ME, Llobet-Navàs D, Llorente A, Lo CH, Lobato-Márquez D, Long Q, Long YC, Loos B, Loos JA, López MG, López-Doménech G, López-Guerrero JA, López-Jiménez AT, López-Pérez Ó, López-Valero I, Lorenowicz MJ, Lorente M, Lorincz P, Lossi L, Lotersztajn S, Lovat PE, Lovell JF, Lovy A, Lőw P, Lu G, Lu H, Lu JH, Lu JJ, Lu M, Lu S, Luciani A, Lucocq JM, Ludovico P, Luftig MA, Luhr M, Luis-Ravelo D, Lum JJ, Luna-Dulcey L, Lund AH, Lund VK, Lünemann JD, Lüningschrör P, Luo H, Luo R, Luo S, Luo Z, Luparello C, Lüscher B, Luu L, Lyakhovich A, Lyamzaev KG, Lystad AH, Lytvynchuk L, Ma AC, Ma C, Ma M, Ma NF, Ma QH, Ma X, Ma Y, Ma Z, MacDougald OA, Macian F, MacIntosh GC, MacKeigan JP, Macleod KF, Maday S, Madeo F, Madesh M, Madl T, Madrigal-Matute J, Maeda A, Maejima Y, Magarinos M, Mahavadi P, Maiani E, Maiese K, Maiti P, Maiuri MC, Majello B, Major MB, Makareeva E, Malik F, Mallilankaraman K, Malorni W, Maloyan A, Mammadova N, Man GCW, Manai F, Mancias JD, Mandelkow EM, Mandell MA, Manfredi AA, Manjili MH, Manjithaya R, Manque P, Manshian BB, Manzano R, Manzoni C, Mao K, Marchese C, Marchetti S, Marconi AM, Marcucci F, Mardente S, Mareninova OA, Margeta M, Mari M, Marinelli S, Marinelli O, Mariño G, Mariotto S, Marshall RS, Marten MR, Martens S, Martin APJ, Martin KR, Martin S, Martin S, Martín-Segura A, Martín-Acebes MA, Martin-Burriel I, Martin-Rincon M, Martin-Sanz P, Martina JA, Martinet W, Martinez A, Martinez A, Martinez J, Martinez Velazquez M, Martinez-Lopez N, Martinez-Vicente M, Martins DO, Martins JO, Martins WK, Martins-Marques T, Marzetti E, Masaldan S, Masclaux-Daubresse C, Mashek DG, Massa V, Massieu L, Masson GR, Masuelli L, Masyuk AI, Masyuk TV, Matarrese P, Matheu A, Matoba S, Matsuzaki S, Mattar P, Matte A, Mattoscio D, Mauriz JL, Mauthe M, Mauvezin C, Maverakis E, Maycotte P, Mayer J, Mazzoccoli G, Mazzoni C, Mazzulli JR, McCarty N, McDonald C, McGill MR, McKenna SL, McLaughlin B, McLoughlin F, McNiven MA, McWilliams TG, Mechta-Grigoriou F, Medeiros TC, Medina DL, Megeney LA, Megyeri K, Mehrpour M, Mehta JL, Meijer AJ, Meijer AH, Mejlvang J, Meléndez A, Melk A, Memisoglu G, Mendes AF, Meng D, Meng F, Meng T, Menna-Barreto R, Menon MB, Mercer C, Mercier AE, Mergny JL, Merighi A, Merkley SD, Merla G, Meske V, Mestre AC, Metur SP, Meyer C, Meyer H, Mi W, Mialet-Perez J, Miao J, Micale L, Miki Y, Milan E, Milczarek M, Miller DL, Miller SI, Miller S, Millward SW, Milosevic I, Minina EA, Mirzaei H, Mirzaei HR, Mirzaei M, Mishra A, Mishra N, Mishra PK, Misirkic Marjanovic M, Misasi R, Misra A, Misso G, Mitchell C, Mitou G, Miura T, Miyamoto S, Miyazaki M, Miyazaki M, Miyazaki T, Miyazawa K, Mizushima N, Mogensen TH, Mograbi B, Mohammadinejad R, Mohamud Y, Mohanty A, Mohapatra S, Möhlmann T, Mohmmed A, Moles A, Moley KH, Molinari M, Mollace V, Møller AB, Mollereau B, Mollinedo F, Montagna C, Monteiro MJ, Montella A, Montes LR, Montico B, Mony VK, Monzio Compagnoni G, Moore MN, Moosavi MA, Mora AL, Mora M, Morales-Alamo D, Moratalla R, Moreira PI, Morelli E, Moreno S, Moreno-Blas D, Moresi V, Morga B, Morgan AH, Morin F, Morishita H, Moritz OL, Moriyama M, Moriyasu Y, Morleo M, Morselli E, Moruno-Manchon JF, Moscat J, Mostowy S, Motori E, Moura AF, Moustaid-Moussa N, Mrakovcic M, Muciño-Hernández G, Mukherjee A, Mukhopadhyay S, Mulcahy Levy JM, Mulero V, Muller S, Münch C, Munjal A, Munoz-Canoves P, Muñoz-Galdeano T, Münz C, Murakawa T, Muratori C, Murphy BM, Murphy JP, Murthy A, Myöhänen TT, Mysorekar IU, Mytych J, Nabavi SM, Nabissi M, Nagy P, Nah J, Nahimana A, Nakagawa I, Nakamura K, Nakatogawa H, Nandi SS, Nanjundan M, Nanni M, Napolitano G, Nardacci R, Narita M, Nassif M, Nathan I, Natsumeda M, Naude RJ, Naumann C, Naveiras O, Navid F, Nawrocki ST, Nazarko TY, Nazio F, Negoita F, Neill T, Neisch AL, Neri LM, Netea MG, Neubert P, Neufeld TP, Neumann D, Neutzner A, Newton PT, Ney PA, Nezis IP, Ng CCW, Ng TB, Nguyen HTT, Nguyen LT, Ni HM, Ní Cheallaigh C, Ni Z, Nicolao MC, Nicoli F, Nieto-Diaz M, Nilsson P, Ning S, Niranjan R, Nishimune H, Niso-Santano M, Nixon RA, Nobili A, Nobrega C, Noda T, Nogueira-Recalde U, Nolan TM, Nombela I, Novak I, Novoa B, Nozawa T, Nukina N, Nussbaum-Krammer C, Nylandsted J, O'Donovan TR, O'Leary SM, O'Rourke EJ, O'Sullivan MP, O'Sullivan TE, Oddo S, Oehme I, Ogawa M, Ogier-Denis E, Ogmundsdottir MH, Ogretmen B, Oh GT, Oh SH, Oh YJ, Ohama T, Ohashi Y, Ohmuraya M, Oikonomou V, Ojha R, Okamoto K, Okazawa H, Oku M, Oliván S, Oliveira JMA, Ollmann M, Olzmann JA, Omari S, Omary MB, Önal G, Ondrej M, Ong SB, Ong SG, Onnis A, Orellana JA, Orellana JA, Orellana-Muñoz S, Ortega-Villaizan MDM, Ortiz-Gonzalez XR, Ortona E, Osiewacz HD, Osman AK, Osta R, Otegui MS, Otsu K, Ott C, Ottobrini L, Ou JJ, Outeiro TF, Oynebraten I, Ozturk M, Pagès G, Pahari S, Pajares M, Pajvani UB, Pal R, Paladino S, Pallet N, Palmieri M, Palmisano G, Palumbo C, Pampaloni F, Pan L, Pan Q, Pan W, Pan X, Panasyuk G, Pandey R, Pandey UB, Pandya V, Paneni F, Pang SY, Panzarini E, Papademetrio DL, Papaleo E, Papinski D, Papp D, Park EC, Park HT, Park JM, Park JI, Park JT, Park J, Park SC, Park SY, Parola AH, Parys JB, Pasquier A, Pasquier B, Passos JF, Pastore N, Patel HH, Patschan D, Pattingre S, Pedraza-Alva G, Pedraza-Chaverri J, Pedrozo Z, Pei G, Pei J, Peled-Zehavi H, Pellegrini JM, Pelletier J, Peñalva MA, Peng D, Peng Y, Penna F, Pennuto M, Pentimalli F, Pereira CM, Pereira GJS, Pereira LC, Pereira de Almeida L, Perera ND, Pérez-Lara Á, Perez-Oliva AB, Pérez-Pérez ME, Periyasamy P, Perl A, Perrotta C, Perrotta I, Pestell RG, Petersen M, Petrache I, Petrovski G, Pfirrmann T, Pfister AS, Philips JA, Pi H, Picca A, Pickrell AM, Picot S, Pierantoni GM, Pierdominici M, Pierre P, Pierrefite-Carle V, Pierzynowska K, Pietrocola F, Pietruczuk M, Pignata C, Pimentel-Muiños FX, Pinar M, Pinheiro RO, Pinkas-Kramarski R, Pinton P, Pircs K, Piya S, Pizzo P, Plantinga TS, Platta HW, Plaza-Zabala A, Plomann M, Plotnikov EY, Plun-Favreau H, Pluta R, Pocock R, Pöggeler S, Pohl C, Poirot M, Poletti A, Ponpuak M, Popelka H, Popova B, Porta H, Porte Alcon S, Portilla-Fernandez E, Post M, Potts MB, Poulton J, Powers T, Prahlad V, Prajsnar TK, Praticò D, Prencipe R, Priault M, Proikas-Cezanne T, Promponas VJ, Proud CG, Puertollano R, Puglielli L, Pulinilkunnil T, Puri D, Puri R, Puyal J, Qi X, Qi Y, Qian W, Qiang L, Qiu Y, Quadrilatero J, Quarleri J, Raben N, Rabinowich H, Ragona D, Ragusa MJ, Rahimi N, Rahmati M, Raia V, Raimundo N, Rajasekaran NS, Ramachandra Rao S, Rami A, Ramírez-Pardo I, Ramsden DB, Randow F, Rangarajan PN, Ranieri D, Rao H, Rao L, Rao R, Rathore S, Ratnayaka JA, Ratovitski EA, Ravanan P, Ravegnini G, Ray SK, Razani B, Rebecca V, Reggiori F, Régnier-Vigouroux A, Reichert AS, Reigada D, Reiling JH, Rein T, Reipert S, Rekha RS, Ren H, Ren J, Ren W, Renault T, Renga G, Reue K, Rewitz K, Ribeiro de Andrade Ramos B, Riazuddin SA, Ribeiro-Rodrigues TM, Ricci JE, Ricci R, Riccio V, Richardson DR, Rikihisa Y, Risbud MV, Risueño RM, Ritis K, Rizza S, Rizzuto R, Roberts HC, Roberts LD, Robinson KJ, Roccheri MC, Rocchi S, Rodney GG, Rodrigues T, Rodrigues Silva VR, Rodriguez A, Rodriguez-Barrueco R, Rodriguez-Henche N, Rodriguez-Rocha H, Roelofs J, Rogers RS, Rogov VV, Rojo AI, Rolka K, Romanello V, Romani L, Romano A, Romano PS, Romeo-Guitart D, Romero LC, Romero M, Roney JC, Rongo C, Roperto S, Rosenfeldt MT, Rosenstiel P, Rosenwald AG, Roth KA, Roth L, Roth S, Rouschop KMA, Roussel BD, Roux S, Rovere-Querini P, Roy A, Rozieres A, Ruano D, Rubinsztein DC, Rubtsova MP, Ruckdeschel K, Ruckenstuhl C, Rudolf E, Rudolf R, Ruggieri A, Ruparelia AA, Rusmini P, Russell RR, Russo GL, Russo M, Russo R, Ryabaya OO, Ryan KM, Ryu KY, Sabater-Arcis M, Sachdev U, Sacher M, Sachse C, Sadhu A, Sadoshima J, Safren N, Saftig P, Sagona AP, Sahay G, Sahebkar A, Sahin M, Sahin O, Sahni S, Saito N, Saito S, Saito T, Sakai R, Sakai Y, Sakamaki JI, Saksela K, Salazar G, Salazar-Degracia A, Salekdeh GH, Saluja AK, Sampaio-Marques B, Sanchez MC, Sanchez-Alcazar JA, Sanchez-Vera V, Sancho-Shimizu V, Sanderson JT, Sandri M, Santaguida S, Santambrogio L, Santana MM, Santoni G, Sanz A, Sanz P, Saran S, Sardiello M, Sargeant TJ, Sarin A, Sarkar C, Sarkar S, Sarrias MR, Sarkar S, Sarmah DT, Sarparanta J, Sathyanarayan A, Sathyanarayanan R, Scaglione KM, Scatozza F, Schaefer L, Schafer ZT, Schaible UE, Schapira AHV, Scharl M, Schatzl HM, Schein CH, Scheper W, Scheuring D, Schiaffino MV, Schiappacassi M, Schindl R, Schlattner U, Schmidt O, Schmitt R, Schmidt SD, Schmitz I, Schmukler E, Schneider A, Schneider BE, Schober R, Schoijet AC, Schott MB, Schramm M, Schröder B, Schuh K, Schüller C, Schulze RJ, Schürmanns L, Schwamborn JC, Schwarten M, Scialo F, Sciarretta S, Scott MJ, Scotto KW, Scovassi AI, Scrima A, Scrivo A, Sebastian D, Sebti S, Sedej S, Segatori L, Segev N, Seglen PO, Seiliez I, Seki E, Selleck SB, Sellke FW, Selsby JT, Sendtner M, Senturk S, Seranova E, Sergi C, Serra-Moreno R, Sesaki H, Settembre C, Setty SRG, Sgarbi G, Sha O, Shacka JJ, Shah JA, Shang D, Shao C, Shao F, Sharbati S, Sharkey LM, Sharma D, Sharma G, Sharma K, Sharma P, Sharma S, Shen HM, Shen H, Shen J, Shen M, Shen W, Shen Z, Sheng R, Sheng Z, Sheng ZH, Shi J, Shi X, Shi YH, Shiba-Fukushima K, Shieh JJ, Shimada Y, Shimizu S, Shimozawa M, Shintani T, Shoemaker CJ, Shojaei S, Shoji I, Shravage BV, Shridhar V, Shu CW, Shu HB, Shui K, Shukla AK, Shutt TE, Sica V, Siddiqui A, Sierra A, Sierra-Torre V, Signorelli S, Sil P, Silva BJA, Silva JD, Silva-Pavez E, Silvente-Poirot S, Simmonds RE, Simon AK, Simon HU, Simons M, Singh A, Singh LP, Singh R, Singh SV, Singh SK, Singh SB, Singh S, Singh SP, Sinha D, Sinha RA, Sinha S, Sirko A, Sirohi K, Sivridis EL, Skendros P, Skirycz A, Slaninová I, Smaili SS, Smertenko A, Smith MD, Soenen SJ, Sohn EJ, Sok 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S, Zwerschke W, Brand-Saberi B, Dong XC, Kenchappa CS, Li Z, Lin Y, Oshima S, Rong Y, Sluimer JC, Stallings CL, Tong CK.", "citedByCount": 2088, "hasFullText": true, "isOpenAccess": false, "meshTerms": [ "Lysosomes", "Animals", "Humans", "Biological Assay", "Autophagy" ], "pmcid": "PMC7996087", "pmid": "33634751", "title": "Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)<sup>1</sup>.", "year": "2021" }, { "abstractText": "The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings in", "authorString": "Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P.", "citedByCount": 2080, "hasFullText": false, "isOpenAccess": false, "meshTerms": [ "Brain", "COS Cells", "PC12 Cells", "Chromosomes, Human, Pair 1", "Cell Nucleus" ], "pmid": "12446870", "title": "Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.", "year": "2003" }, { "abstractText": "Neuroinflammation is associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is het", "authorString": "Kwon HS, Koh SH.", "citedByCount": 1755, "hasFullText": true, "isOpenAccess": true, "meshTerms": [ "Astrocytes", "Microglia", "Animals", "Humans", "Neurodegenerative Diseases" ], "pmcid": "PMC7689983", "pmid": "33239064", "title": "Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes.", "year": "2020" }, { "abstractText": "Oxidative stress plays an important role in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Disruptions in the physiologic maintenance of the redox potential in neurons interfere with several biological processes, ultimately leading to cell death. 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Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59%", "label": "10510 participants", "pmid": "39074992" }, { "context": "genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not", "label": "p=0.021", "pmid": "35893043" }, { "context": "However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were", "label": "p=0.025", "pmid": "35893043" }, { "context": "using baseline Parkinson's Progression Markers Initiative (PPMI) data (n = 390), integrating blood RNA sequencing (RNA-seq) and clinical features to predict", "label": "n=390", "pmid": "41789394" }, { "context": "neuroinflammation, and autophagy. Results On an independent test set (n = 78), the model achieved a Coefficient of Determination (R²) of 0.551 and Mean", "label": "n=78", "pmid": "41789394" }, { "context": "The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were", "label": "n=279", "pmid": "32568194" }, { "context": "real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in", "label": "1.5-fold", "pmid": "26483988" }, { "context": "genetic variants in six PARK genes in PD patients. In total 381 individuals (173 patients, 208 controls) were genotyped for p.Gly2019Ser and p.Gly2385Arg variants of", "label": "173 patients", "pmid": "24729340" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results", "label": "OR=1.67", "pmid": "40750593" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results highlight", "label": "p=0.03", "pmid": "40750593" } ], "totalItems": 14 } }, "evidenceScorecard": { "citationWarnings": 0, "consensus": { "consensusLabel": "Strong", "consensusRatio": 1, "contentionLabel": "Low", "contentionRatio": 0, "contradictWeight": 0, "mixedWeight": 0, "netConsensus": 1, "supportWeight": 54.02, "totalWeight": 54.02 }, "hypotheses": { "total": 2, "withContention": 0, "withContradictions": 0, "withMixed": 0, "withSupport": 2 }, "insights": { "total": 5, "uniqueContradictingPmids": 0, "uniqueMixedPmids": 0, "withContention": 0, "withContradictions": 0, "withMixed": 0, "withSupport": 5, "withoutCitations": 0 }, "papers": { "contradict": 0, "mixed": 0, "neutral": 15, "support": 33 } }, "evidenceSummary": { "papersWithEvidence": 9, "topItems": [ { "context": "carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed", "label": "34 patients", "pmid": "33459660" }, { "context": "response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome,", "label": "293 patients", "pmid": "33459660" }, { "context": "frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of", "label": "200 patients", "pmid": "33459660" }, { "context": "MAPT, PARK2, PARK7, PINK1 PLA2G6, SNCA, UCHL1, and VPS35 were analyzed in 62 patients (P) and 69 age-matched controls from the researched area (C1). Variants were", "label": "62 patients", "pmid": "35054514" }, { "context": "at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59%", "label": "10510 participants", "pmid": "39074992" }, { "context": "genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not", "label": "p=0.021", "pmid": "35893043" }, { "context": "However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were", "label": "p=0.025", "pmid": "35893043" }, { "context": "using baseline Parkinson's Progression Markers Initiative (PPMI) data (n = 390), integrating blood RNA sequencing (RNA-seq) and clinical features to predict", "label": "n=390", "pmid": "41789394" }, { "context": "neuroinflammation, and autophagy. Results On an independent test set (n = 78), the model achieved a Coefficient of Determination (R²) of 0.551 and Mean", "label": "n=78", "pmid": "41789394" }, { "context": "The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were", "label": "n=279", "pmid": "32568194" }, { "context": "real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in", "label": "1.5-fold", "pmid": "26483988" }, { "context": "genetic variants in six PARK genes in PD patients. In total 381 individuals (173 patients, 208 controls) were genotyped for p.Gly2019Ser and p.Gly2385Arg variants of", "label": "173 patients", "pmid": "24729340" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results", "label": "OR=1.67", "pmid": "40750593" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results highlight", "label": "p=0.03", "pmid": "40750593" } ], "totalItems": 14 }, "fdaRegulatoryEnrichment": { "entrectinib": { "contextMatched": true, "designations": [ { "indication": "native therapy. This indication is approved under accelerated approval based on tumor response rate ", "type": "accelerated" }, { "indication": "Parkinson's disease", "type": "priority" } ], "drug": "ENTRECTINIB", "hasAccelerated": true, "hasBreakthrough": false, "hasData": true, "hasFastTrack": false, "hasOrphan": false, "hasPriorityReview": true, "narrative": "ENTRECTINIB FDA designations: Accelerated Approval, Priority Review.", "source": "FDA OpenFDA Regulatory Designations" }, "palbociclib": { "contextMatched": true, "designations": [ { "indication": "Parkinson's disease", "type": "priority" } ], "drug": "PALBOCICLIB", "hasAccelerated": false, "hasBreakthrough": false, "hasData": true, "hasFastTrack": false, "hasOrphan": false, "hasPriorityReview": true, "narrative": "PALBOCICLIB FDA designations: Priority Review.", "source": "FDA OpenFDA Regulatory Designations" }, "vandetanib": { "contextMatched": true, "designations": [ { "indication": "Parkinson's disease", "type": "priority" } ], "drug": "VANDETANIB", "hasAccelerated": false, "hasBreakthrough": false, "hasData": true, "hasFastTrack": false, "hasOrphan": false, "hasPriorityReview": true, "narrative": "VANDETANIB FDA designations: Priority Review.", "source": "FDA OpenFDA Regulatory Designations" } }, "gdscEnrichment": { "LRRK2": { "bestCompound": "CHEMBL4546504", "bestIC50_nM": 0, "dataSource": "ChEMBL", "gene": "LRRK2", "hasData": true, "ic50Records": [ { "assayDescription": "Inhibition of recombinant human GST-tagged LRRK2 G2019S mutant catalytic domain ", "assayType": "A", "drug": "CHEMBL4546504", "ic50_nM": 0 }, { "assayDescription": "Inhibition of recombinant human GST-tagged LRRK2 catalytic domain (970 to 2527 r", "assayType": "A", "drug": "CHEMBL4546504", "ic50_nM": 0 }, { "assayDescription": "Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein l", "assayType": "B", "drug": "CHEMBL5189225", "ic50_nM": 0 }, { "assayDescription": "Inhibition of GST-tagged truncated human LRRK2 G2019S mutant using fluorescein l", "assayType": "B", "drug": "CHEMBL5195441", "ic50_nM": 0 }, { "assayDescription": "Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 ", "assayType": "B", "drug": "CHEMBL5405380", "ic50_nM": 0 }, { "assayDescription": "Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 ", "assayType": "B", "drug": "CHEMBL5088471", "ic50_nM": 0 }, { "assayDescription": "Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 ", "assayType": "B", "drug": "CHEMBL5433289", "ic50_nM": 0 }, { "assayDescription": "Inhibition of recombinant N-terminal GST-fused LRRK2 G2109S mutant (970 to 2527 ", "assayType": "B", "drug": "CHEMBL5407732", "ic50_nM": 0 } ], "knownDrugs": [], "narrative": "LRRK2 ChEMBL bioactivity: 8 IC50 records. Most potent: CHEMBL4546504 IC50 = 0 nM. Compounds: CHEMBL4546504, CHEMBL4546504, CHEMBL5189225, CHEMBL5195441.", "pgxAnnotations": 0, "sensitivityDrugs": [ { "category": "potency", "drug": "CHEMBL4546504", "ic50_nM": 0 }, { "category": "potency", "drug": "CHEMBL4546504", "ic50_nM": 0 }, { "category": "potency", "drug": "CHEMBL5189225", "ic50_nM": 0 } ], "source": "ChEMBL bioactivity (IC50)" }, "PARK7": { "bestCompound": "CHEMBL5559797", "bestIC50_nM": 19, "dataSource": "ChEMBL", "gene": "PARK7", "hasData": true, "ic50Records": [ { "assayDescription": "Inhibition of PARK7 (unknown origin) using DiFUMAc as substrate preincubated for", "assayType": "B", "drug": "CHEMBL5559797", "ic50_nM": 19 }, { "assayDescription": "Inhibition of PARK7 (unknown origin) using DiFUMAc as substrate preincubated for", "assayType": "B", "drug": "CHEMBL5559582", "ic50_nM": 21 }, { "assayDescription": "Inhibition of pET3a-His-tagged DJ1 (unknown origin) expressed in Escherichia col", "assayType": "B", "drug": "CHEMBL5202724", "ic50_nM": 55 }, { "assayDescription": "Inhibition of pET3a-His-tagged DJ1 (unknown origin) expressed in Escherichia col", "assayType": "B", "drug": "CHEMBL406190", "ic50_nM": 63 }, { "assayDescription": "Inhibition of pET3a-His-tagged DJ1 (unknown origin) expressed in Escherichia col", "assayType": "B", "drug": "CHEMBL5192433", "ic50_nM": 85 }, { "assayDescription": "Inhibition of pET3a-His-tagged DJ1 (unknown origin) expressed in Escherichia col", "assayType": "B", "drug": "CHEMBL5176828", "ic50_nM": 118 }, { "assayDescription": "Inhibition of pET3a-His-tagged DJ1 (unknown origin) expressed in Escherichia col", "assayType": "B", "drug": "CHEMBL5172713", "ic50_nM": 118 }, { "assayDescription": "Inhibition of PARK7 (unknown origin) using DiFUMAc as substrate preincubated for", "assayType": "B", "drug": "JYQ88", "ic50_nM": 120 } ], "knownDrugs": [], "narrative": "PARK7 ChEMBL bioactivity: 8 IC50 records. Most potent: CHEMBL5559797 IC50 = 19 nM. Compounds: CHEMBL5559797, CHEMBL5559582, CHEMBL5202724, CHEMBL406190.", "pgxAnnotations": 0, "sensitivityDrugs": [ { "category": "potency", "drug": "CHEMBL5559797", "ic50_nM": 19 }, { "category": "potency", "drug": "CHEMBL5559582", "ic50_nM": 21 }, { "category": "potency", "drug": "CHEMBL5202724", "ic50_nM": 55 } ], "source": "ChEMBL bioactivity (IC50)" }, "SNCA": { "bestCompound": "CHEMBL5286894", "bestIC50_nM": 1, "dataSource": "ChEMBL", "gene": "SNCA", "hasData": true, "ic50Records": [ { "assayDescription": "Inhibition of Alpha-synuclein (unknown origin) fibrils", "assayType": "B", "drug": "CHEMBL5286894", "ic50_nM": 1 }, { "assayDescription": "Binding affinity to human alpha-synuclein expressed in Escherichia coli BL21 (DE", "assayType": "B", "drug": "CHEMBL2063787", "ic50_nM": 134 }, { "assayDescription": "Inhibition of alpha-synuclein fibril formation (unknown origin) incubated for 24", "assayType": "B", "drug": "RETINAL", "ic50_nM": 190 }, { "assayDescription": "Inhibition of alpha-synuclein fibril formation (unknown origin) incubated for 24", "assayType": "B", "drug": "RETINOL", "ic50_nM": 190 }, { "assayDescription": "Binding affinity to human alpha-synuclein expressed in Escherichia coli BL21 (DE", "assayType": "B", "drug": "CHEMBL2063797", "ic50_nM": 204 }, { "assayDescription": "Inhibition of alpha-synuclein aggregation (unknown origin) incubated for 8 days ", "assayType": "B", "drug": "NORDIHYDROGUAIARETIC ACID", "ic50_nM": 210 }, { "assayDescription": "Inhibition of alpha-synuclein fibril formation (unknown origin) incubated for 24", "assayType": "B", "drug": "ROSMARINIC ACID", "ic50_nM": 210 }, { "assayDescription": "Inhibition of alpha-synuclein fibril formation (unknown origin) incubated for 24", "assayType": "B", "drug": "CURCUMIN", "ic50_nM": 220 } ], "knownDrugs": [], "narrative": "SNCA ChEMBL bioactivity: 8 IC50 records. Most potent: CHEMBL5286894 IC50 = 1 nM. Compounds: CHEMBL5286894, CHEMBL2063787, RETINAL, RETINOL.", "pgxAnnotations": 0, "sensitivityDrugs": [ { "category": "potency", "drug": "CHEMBL5286894", "ic50_nM": 1 }, { "category": "potency", "drug": "CHEMBL2063787", "ic50_nM": 134 }, { "category": "potency", "drug": "RETINAL", "ic50_nM": 190 } ], "source": "ChEMBL bioactivity (IC50)" } }, "geneResolution": { "ok": true, "proteinResolution": [ { "geneSymbol": "SNCA", "length": 140, "reason": null, "sequence": "MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDPDNEAYEMPSEEGYQDYEPEA", "status": "ok", "uniprotId": "P37840" }, { "geneSymbol": "LRRK2", "length": 2527, "reason": "Sequence length 2527 > 1022; truncated for SAE.", "sequence": "MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNIHVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILKMLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVEVLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQQYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWHRKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASANALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIMAAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKNDIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQEIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLARMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEGSFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLRSSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKENKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE", "status": "sequence_truncated", "uniprotId": "Q5S007" }, { "geneSymbol": "PARK7", "length": 189, "reason": null, "sequence": "MASKRALVILAKGAEEMETVIPVDVMRRAGIKVTVAGLAGKDPVQCSRDVVICPDASLEDAKKEGPYDVVVLPGGNLGAQNLSESAAVKEILKEQENRKGLIAAICAGPTALLAHEIGFGSKVTTHPLAKDKMMNGGHYTYSENRVEKDGLILTSRGPGTSFEFALAIVEALNGKEVAAQVKAPLVLKD", "status": "ok", "uniprotId": "Q99497" } ], "resolved": [ { "alias_override": null, "aliases": [ "SNCA", "NACP", "PARK1" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000145335", "ensembl_id": "ENSG00000145335", "ensembl_ids_uniprot": [ "ENST00000336904.7", "ENST00000345009.8", "ENST00000394986.5", "ENST00000394989.6", "ENST00000394991.8", "ENST00000420646.6", "ENST00000505199.5", "ENST00000506244.5", "ENST00000508895.5", "ENST00000618500.4", "ENST00000673718.1" ], "function": "Neuronal protein that plays several roles in synaptic activity such as regulation of synaptic vesicle trafficking and subsequent neurotransmitter release (PubMed:20798282, PubMed:26442590, PubMed:28288128, PubMed:30404828). Participates as a monomer in synaptic vesicle exocytosis by enhancing ves...", "hgncId": "HGNC:11138", "hgnc_id": "HGNC:11138", "identifierAgreement": 0.8, "input": "SNCA", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "Alpha-synuclein", "ncbiGeneId": "6622", "ncbi_gene_id": "6622", "proteinLength": 140, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "SNCA", "subcellularLocation": "Cytoplasm", "suggestions": [ { "name": "synuclein alpha", "symbol": "SNCA", "uniprotId": null }, { "name": "SNCAIP antisense RNA 2", "symbol": "SNCAIP-AS2", "uniprotId": null }, { "name": "SNCAIP antisense RNA 3", "symbol": "SNCAIP-AS3", "uniprotId": null } ], "symbol": "SNCA", "tissueExpression": "Highly expressed in presynaptic terminals in the central nervous system. Expressed principally in brain", "uniprotId": "P37840", "uniprot_id": "P37840" }, { "alias_override": null, "aliases": [ "LRRK2", "PARK8" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000188906", "ensembl_id": "ENSG00000188906", "ensembl_ids_uniprot": [ "ENST00000298910.12" ], "function": "Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, PubMed:23395371, PubMed:24687852, Pub...", "hgncId": "HGNC:18618", "hgnc_id": "HGNC:18618", "identifierAgreement": 0.8, "input": "LRRK2", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "Leucine-rich repeat serine/threonine-protein kinase 2", "ncbiGeneId": "120892", "ncbi_gene_id": "120892", "proteinLength": 2527, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "LRRK2", "subcellularLocation": "Cytoplasmic vesicle", "suggestions": [ { "name": "leucine rich repeat kinase 2", "symbol": "LRRK2", "uniprotId": null }, { "name": "LRRK2 divergent transcript", "symbol": "LRRK2-DT", "uniprotId": null }, { "name": "novel transcript, sense intronic to LRRK2", "symbol": "ENSG00000289310", "uniprotId": null } ], "symbol": "LRRK2", "tissueExpression": "Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed in neutrophils (at pr...", "uniprotId": "Q5S007", "uniprot_id": "Q5S007" }, { "alias_override": null, "aliases": [ "PARK7" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000116288", "ensembl_id": "ENSG00000116288", "ensembl_ids_uniprot": [ "ENST00000338639.10", "ENST00000377488.5", "ENST00000377491.5", "ENST00000493373.5", "ENST00000493678.5" ], "function": "Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease (PubMed:12796482, PubMed:17015834, PubMed:18711745, PubMed:19229105, ...", "hgncId": "HGNC:16369", "hgnc_id": "HGNC:16369", "identifierAgreement": 0.8, "input": "PARK7", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "Parkinson disease protein 7", "ncbiGeneId": "11315", "ncbi_gene_id": "11315", "proteinLength": 189, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "PARK7", "subcellularLocation": "Cell membrane", "suggestions": [ { "name": "Parkinsonism associated deglycase", "symbol": "PARK7", "uniprotId": null }, { "name": "PARK7 pseudogene 1", "symbol": "PARK7P1", "uniprotId": null }, { "name": "PARK7 pseudogene 2", "symbol": "PARK7P2", "uniprotId": null } ], "symbol": "PARK7", "tissueExpression": "Highly expressed in pancreas, kidney, skeletal muscle, liver, testis and heart. Detected at slightly lower levels in placenta and brain (at protein level). Detected in astrocytes, Sertoli cells, sp...", "uniprotId": "Q99497", "uniprot_id": "Q99497" } ], "unresolved": [], "usableSymbols": [ "SNCA", "LRRK2", "PARK7" ] }, "geneTherapy": { "rankings": [ { "bestModality": "CRISPR-Cas9", "bestScore": 55, "classification": "unknown", "gene": "PARK7", "hasClinicalPrecedent": false, "isEssential": false, "recommendation": "Moderate candidate — CRISPR-Cas9 feasible with validated delivery system.", "scores": { "aav": { "bestSerotype": "AAV9", "rationale": "AAV delivery of PARK7 is exploratory. Confirm coding sequence ≤4.7 kb and tissue tropism compatibility.", "score": 38 }, "baseEditing": { "rationale": "Base editing requires specific point mutation target. 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Check mutation landscape for actionable variants.", "score": 50 }, "crispr": { "rationale": "CRISPR KO feasibility depends on validated tumour-specific guides.", "score": 50 }, "primeEditing": { "rationale": "Prime editing applicable for small precise corrections. Efficiency lower than base editing for single-base changes.", "score": 47 } }, "therapeuticIndex": "unknown" }, { "bestModality": "CRISPR-Cas9", "bestScore": 50, "classification": "unknown", "gene": "SNCA", "hasClinicalPrecedent": false, "isEssential": false, "recommendation": "Moderate candidate — CRISPR-Cas9 feasible with validated delivery system.", "scores": { "aav": { "bestSerotype": "AAV9", "rationale": "AAV delivery of SNCA is exploratory. Confirm coding sequence ≤4.7 kb and tissue tropism compatibility.", "score": 30 }, "baseEditing": { "rationale": "Base editing requires specific point mutation target. Check mutation landscape for actionable variants.", "score": 50 }, "crispr": { "rationale": "CRISPR KO feasibility depends on validated tumour-specific guides.", "score": 50 }, "primeEditing": { "rationale": "Prime editing applicable for small precise corrections. Efficiency lower than base editing for single-base changes.", "score": 47 } }, "therapeuticIndex": "unknown" } ], "strongCandidates": 0, "topTarget": { "gene": "PARK7", "modality": "CRISPR-Cas9", "precedented": false, "recommendation": "Moderate candidate — CRISPR-Cas9 feasible with validated delivery system.", "score": 55 }, "totalGenes": 3 }, "generatedAtIso": "2026-05-01T15:02:05.806Z", "genes": [ { "centrality": 0.513417119032592, "depMapEssentiality": { "essentialFraction": 0.004, "isStrongTarget": false, "meanChronos": -0.149, "narrative": "PARK7 DepMap Chronos score: mean -0.149 across 1183 cell lines. Essential in 0% of lines (score ≤ -0.5). Classification: Non-essential / poor target. 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Most dependent tissues: adrenal gland (-0.016), testis (0.059), hepatopancreatic ampulla (0.089).", "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.016, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": 0.059, "tissue": "testis" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": 0.089, "tissue": "hepatopancreatic ampulla" }, { "cellLineCount": 47, "essentialFraction": 0, "meanScore": 0.113, "tissue": "pancreas" }, { "cellLineCount": 63, "essentialFraction": 0, "meanScore": 0.117, "tissue": "intestine" }, { "cellLineCount": 59, "essentialFraction": 0, "meanScore": 0.121, "tissue": "internal female genitalia" } ] }, "function": "Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, PubMed:23395371, PubMed:24687852, Pub...", "gtexExpression": null, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.95, "monarchAssociations": { "contextRelevantCount": 4, "narrative": "SNCA is associated with 6 disease(s) in Monarch (OMIM/HPO/Orphanet). 4 match(es) to disease context \"Parkinson's disease\". 15 HPO phenotype(s) including: Lewy bodies, Dysphagia, Micrographia.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0100315", "name": "Lewy bodies", "onset": null }, { "frequency": null, "hpoId": "HP:0002015", "name": "Dysphagia", "onset": null }, { "frequency": null, "hpoId": "HP:0031908", "name": "Micrographia", "onset": null }, { "frequency": null, "hpoId": "HP:0000738", "name": "Hallucinations", "onset": null }, { "frequency": null, "hpoId": "HP:0002067", "name": "Bradykinesia", "onset": null } ], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0008199", "name": "late-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0017279", "name": "young-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0011562", "name": "autosomal dominant Parkinson disease 4", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008200", "name": "autosomal dominant Parkinson disease 1", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0009830", "name": "parkinsonian-pyramidal syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 6 }, "name": "Leucine-rich repeat serine/threonine-protein kinase 2", "symbol": "LRRK2", "syntheticLethality": null, "tissueExpression": "Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). 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Most dependent tissues: adrenal gland (-0.438), testis (-0.238), prostate gland (-0.208).", "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.438, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": -0.238, "tissue": "testis" }, { "cellLineCount": 10, "essentialFraction": 0, "meanScore": -0.208, "tissue": "prostate gland" }, { "cellLineCount": 2, "essentialFraction": 0, "meanScore": -0.181, "tissue": "mammalian vulva" }, { "cellLineCount": 47, "essentialFraction": 0, "meanScore": -0.18, "tissue": "pancreas" }, { "cellLineCount": 45, "essentialFraction": 0, "meanScore": -0.175, "tissue": "Peripheral Nervous System" } ] }, "function": "Multifunctional protein with controversial molecular function which plays an important role in cell protection against oxidative stress and cell death acting as oxidative stress sensor and redox-sensitive chaperone and protease (PubMed:12796482, PubMed:17015834, PubMed:18711745, PubMed:19229105, ...", "gtexExpression": null, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.87, "monarchAssociations": { "contextRelevantCount": 2, "narrative": "LRRK2 is associated with 2 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"Parkinson's disease\". ", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0017279", "name": "young-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008199", "name": "late-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 2 }, "name": "Parkinson disease protein 7", "symbol": "PARK7", "syntheticLethality": null, "tissueExpression": "Highly expressed in pancreas, kidney, skeletal muscle, liver, testis and heart. Detected at slightly lower levels in placenta and brain (at protein level). Detected in astrocytes, Sertoli cells, sp...", "uniprotId": "Q99497" } ], "gnomadAncestryEnrichment": null, "gnomadConstraintEnrichment": null, "gnomadConstraints": { "LRRK2": { "available": true, "citation": "Karczewski et al. Nature 2020; gnomAD v4.0", "constraintColor": "#16a34a", "constraintLabel": "Loss-of-function tolerant", "constraintLevel": "tolerant", "expectedLof": 302.56110946405636, "geneSymbol": "LRRK2", "loeuf": 0.754, "observedLof": 203, "oeLof": 0.671, "pLI": 0, "source": "gnomAD", "therapeuticWindow": "Wide — loss-of-function well-tolerated in human population; inhibition safer", "tooltip": "pLI=0.00, LOEUF=0.75 (gnomAD v4). Wide — loss-of-function well-tolerated in human population; inhibition safer." }, "PARK7": { "available": true, "citation": "Karczewski et al. 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Wide — loss-of-function well-tolerated in human population; inhibition safer." } }, "goEnrichment": { "LRRK2": { "annotations": [ { "assignedBy": [ "GO_Central" ], "goId": "GO:0035556", "goTerm": "intracellular signal transduction", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:1900242", "goTerm": "regulation of synaptic vesicle endocytosis", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0060828", "goTerm": "regulation of canonical Wnt signaling pathway", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0005886", "goTerm": "plasma membrane", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0007029", "goTerm": "endoplasmic reticulum organization", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0010508", "goTerm": "positive regulation 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"molecularFunction": 0 }, "computationalEvidence": 11, "experimentalEvidence": 0, "topComponents": [], "topFunctions": [], "topProcesses": [] }, "totalAnnotations": 11 }, "PARK7": { "annotations": [ { "assignedBy": [ "GO_Central" ], "goId": "GO:0016684", "goTerm": "oxidoreductase activity, acting on peroxide as acceptor", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:1903189", "goTerm": "glyoxal metabolic process", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0005739", "goTerm": "mitochondrion", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0005737", "goTerm": "cytoplasm", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0005634", "goTerm": "nucleus", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0046295", "goTerm": "glycolate 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"reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0043679", "goTerm": "axon terminus", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0050808", "goTerm": "synapse organization", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0005737", "goTerm": "cytoplasm", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0048489", "goTerm": "synaptic vesicle transport", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0048488", "goTerm": "synaptic vesicle endocytosis", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:0001963", "goTerm": "synaptic transmission, dopaminergic", "isExperimental": false, "reference": "UniProtKB" }, { "assignedBy": [ "GO_Central" ], "goId": "GO:1903136", "goTerm": "cuprous ion binding", "isExperimental": false, "reference": "UniProtKB" } ], "gene": "SNCA", "geneId": "UniProtKB:A0A2I2U480", "source": "Gene Ontology Consortium", "summary": { "byAspect": { "biologicalProcess": 0, "cellularComponent": 0, "molecularFunction": 0 }, "computationalEvidence": 10, "experimentalEvidence": 0, "topComponents": [], "topFunctions": [], "topProcesses": [] }, "totalAnnotations": 10 } }, "gtexEnrichment": null, "gwasEnrichment": null, "hgncEnrichment": { "LRRK2": { "aliasSymbols": [ "ROCO2", "DKFZp434H2111", "FLJ45829", "RIPK7" ], "chromosomalLocation": "12q12", "ensemblId": "ENSG00000188906", "entrezId": "120892", "gene": "LRRK2", "geneFamily": [], "hasData": true, "hgncId": "HGNC:18618", "locusGroup": "protein-coding gene", "locusType": "gene with protein product", "narrative": "LRRK2 (HGNC:18618): \"leucine rich repeat kinase 2\", gene with protein product, chr12q12. Aliases: ROCO2, DKFZp434H2111, FLJ45829.", "officialName": "leucine rich repeat kinase 2", "prevSymbols": [ "PARK8" ], "source": "HGNC" }, "PARK7": { "aliasSymbols": [ "DJ-1", "DJ1", "GATD2" ], "chromosomalLocation": "1p36.23", "ensemblId": "ENSG00000116288", "entrezId": "11315", "gene": "PARK7", "geneFamily": [], "hasData": true, "hgncId": "HGNC:16369", "locusGroup": "protein-coding gene", "locusType": "gene with protein product", "narrative": "PARK7 (HGNC:16369): \"Parkinsonism associated deglycase\", gene with protein product, chr1p36.23. Aliases: DJ-1, DJ1, GATD2.", "officialName": "Parkinsonism associated deglycase", "prevSymbols": [], "source": "HGNC" }, "SNCA": { "aliasSymbols": [ "NACP", "PD1" ], "chromosomalLocation": "4q22.1", "ensemblId": "ENSG00000145335", "entrezId": "6622", "gene": "SNCA", "geneFamily": [], "hasData": true, "hgncId": "HGNC:11138", "locusGroup": "protein-coding gene", "locusType": "gene with protein product", "narrative": "SNCA (HGNC:11138): \"synuclein alpha\", gene with protein product, chr4q22.1. 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PARK7 shows protein gain in CPTAC Parkinson Brain Proteome. 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"do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.19, "calibratedConfidence": 0.076, "calibrationDelta": -0.114, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [], "geneSymbol": "LRRK2", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0, "mechanismId": "uncharacterized_LRRK2_1", "notes": [ "Base counterfactual score 0.19", "Hypothesis prior 0 from bucket:very_low", "Prediction prior 0.138 from disease_specific", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Confidence de-escalated because empirical support remains limited" ], "recommendedDoOperator": "do(LRRK2=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0 }, "hypothesis": { "note": "Observed accuracy from the Very low (<0.40) hypothesis bucket", "score": 0, "source": "bucket:very_low" }, "prediction": { "note": "Disease-level prospective prediction prior (113 checked predictions)", "score": 0.1378, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "Parkinson's disease", "evidenceTier": "none", "gene": "LRRK2", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } } ], "summary": { "averageCalibratedConfidence": 0.159, "deescalatedCount": 9, "directlyCalibratedCount": 0, "narrative": "GaiaLab recalibrated intervention confidence for 9 routes using outcome history, disease-level prediction follow-through, and orthogonal evidence support. Top calibrated targets: PARK7.", "topCalibratedTargets": [ "PARK7" ] }, "trackerPriors": { "diseasePredictionResearchDirectionRate": 0.159, "diseasePredictionTrialMatchRate": 0.106, "hypothesisAccuracy": 0, "totalDiseaseCheckedPredictions": 113, "totalValidatedHypotheses": 0, "workspaceObservedAccuracy": null, "workspaceValidatedHypotheses": 0 } }, "interventionSummary": { "available": true, "averageCounterfactualScore": 0.265, "narrative": "Top intervention-ready genes for Parkinson's disease are PARK7 based on pathway anchoring, dependency, structure, and variant directionality.", "preferredModes": [ { "count": 9, "mode": "selective_modulation" } ], "topGenes": [ "PARK7" ], "totalCounterfactuals": 9 }, "ioResistanceProfile": null, "ioResponseScore": null, "jasparEnrichment": { "LRRK2": { "gene": "LRRK2", "hasData": true, "isTF": true, "motifs": [ { "matrix_id": "MA0634.1", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0634.2", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0007.2", "name": "AR", "tf_class": null, "tf_family": null } ], "narrative": "LRRK2 is a unknown TF with JASPAR CORE motif MA0634.1 (ALX3).", "source": "JASPAR 2024", "tfClass": "unknown", "topMotif": { "collection": "CORE", "matrix_id": "MA0634.1", "name": "ALX3", "species": "", "tf_class": null, "tf_family": null } }, "PARK7": { "gene": "PARK7", "hasData": true, "isTF": true, "motifs": [ { "matrix_id": "MA0634.1", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0634.2", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0007.2", "name": "AR", "tf_class": null, "tf_family": null } ], "narrative": "PARK7 is a unknown TF with JASPAR CORE motif MA0634.1 (ALX3).", "source": "JASPAR 2024", "tfClass": "unknown", "topMotif": { "collection": "CORE", "matrix_id": "MA0634.1", "name": "ALX3", "species": "", "tf_class": null, "tf_family": null } }, "SNCA": { "gene": "SNCA", "hasData": true, "isTF": true, "motifs": [ { "matrix_id": "MA0634.1", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0634.2", "name": "ALX3", "tf_class": null, "tf_family": null }, { "matrix_id": "MA0007.2", "name": "AR", "tf_class": null, "tf_family": null } ], "narrative": "SNCA is a unknown TF with JASPAR CORE motif MA0634.1 (ALX3).", "source": "JASPAR 2024", "tfClass": "unknown", "topMotif": { "collection": "CORE", "matrix_id": "MA0634.1", "name": "ALX3", "species": "", "tf_class": null, "tf_family": null } } }, "lead": { "drug": { "drug": "PALBOCICLIB", "score": 50 }, "pathway": { "id": "pathway-0", "name": "Alpha-synuclein aggregation and Lewy body formation" }, "strategy": { "id": "strategy-0", "label": "LRRK2 kinase inhibitors for SNCA and LRRK2 mutation carriers" } }, "leadingResearchers": [], "learningMemory": null, "lincsEnrichment": null, "matchingTrials": [ { "briefSummary": "The goal of this Phase 2 clinical trial is to investigate the efficacy and safety of NEU-411 in men and women aged 40-80 years with early Parkinson's Disease (PD) who have predicted elevations in the activity of the \"leucine-rich repeat kinase 2\" (\"LRRK2\" for short) pathway based on their genetic profile. A DNA test will be used to identify the \"LRRK2-driven\" population with predicted elevation in the LRRK2 pathway.", "completionDate": "2027-09", "conditionSummary": "Parkinson Disease · Parkinson · Idiopathic Parkinson Disease", "conditions": [ "Parkinson Disease", "Parkinson", "Idiopathic Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 150, "firstPostedDate": "2024-11-08", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "NEU-411", "Placebo" ], "nctId": "NCT06680830", "phase": "Phase 2", "primaryCompletionDate": "2026-09", "primaryPurpose": "TREATMENT", "startDate": "2025-01-17", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "NEU-411-PD201 is a Phase 2, randomized, placebo-controlled, proof-of-concept study and open-label extension (OLE) in participants with early Parkinson's Disease (PD) who have LRRK2-driven PD as measured by an investigational companion diagnostic genetic test (CDx). The study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of NEU-411, an orally-administered, potent, selective, bioavailable, highly permeable, brain penetrant, small molecule inhibitor of LRRK2 activity as compared to placebo.\n\nAfter participants are screened for inclusion in the randomized, placebo-controlled portion of the study, approximately 150 participants will be randomized in a 1:1 allocation to NEU-411 30 mg once per day or placebo for a 52-week treatment period with a safety follow-up visit within 2 weeks after the last treatment visit. Eligible participants may enroll in the OLE and receive treatment for an additional 26 weeks.", "title": "A Phase 2 Study and Open-Label Extension of NEU-411 in Companion Diagnostic-Positive Participants With Early Parkinson's Disease", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06680830", "whyStopped": "" }, { "briefSummary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "completionDate": "2028-02-28", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro" ] }, "enrollmentCount": 50, "firstPostedDate": "2024-09-19", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122 225 mg", "BIIB122-Matching Placebo" ], "nctId": "NCT06602193", "phase": "Phase 2", "primaryCompletionDate": "2026-04-30", "primaryPurpose": "TREATMENT", "startDate": "2024-10-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This Phase 2a, multicenter, randomized, 12-week double-blind, placebo-controlled, parallel-group study, followed by an OLE, is designed to evaluate the safety, tolerability, and pharmacodynamic effects of BIIB122 in participants with LRRK2-PD. LRRK2-PD is defined as Parkinson's Disease (PD) in individuals who are heterozygous or homozygous carriers of a pathogenic LRRK2 variant that increases LRRK2 kinase activity.", "title": "Safety and Pharmacodynamic Effects of BIIB122 in Participants With LRRK2-Associated Parkinson's Disease (LRRK2-PD)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06602193", "whyStopped": "" }, { "briefSummary": "In this study, researchers will learn more about BIIB122 in participants with early-stage Parkinson's disease (PD). The study will include adults aged 30 to 80 who were diagnosed with PD within 2 years of starting the study.\n\nThe main objective of the study is to learn about the effect BIIB122 has on slowing down the worsening of PD symptoms. The main question researchers want to answer is:\n\n\\- How long does it take for PD symptoms to worsen during BIIB122 treatment?\n\nResearchers will answer this and other questions by measuring the symptoms of PD over time using a variety of scoring tools. These include the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the modified Schwab and England Activities of Daily Living Scale (mSE-ADL).\n\nThe MDS-UPDRS is used to measure symptoms of PD. It has 4 parts: Part I, II, III, and IV. Each part measures different aspects of motor and non-motor symptoms. The mSE-ADL measures a participant's ability to perform daily activities or personal chores.\n\nResearchers will also learn more about the safety of BIIB122. They will check participants for adverse events. Adverse events are unwanted health problems that may or may not be caused by the study drug.\n\nThe study will be done as follows:\n\n* Participants will be randomly assigned to take either BIIBB122 or placebo. A placebo looks like the study drug but contains no real medicine.\n* Neither the researchers nor the participants will know if the participants are receiving BIIB122 or placebo.\n* Participants will take BIIB122 or placebo tablets by mouth once a day.\n* The treatment period for each participant will last between 48 and 144 weeks.\n* There will be a safety follow-up period for 2 weeks after the last dose of BIIB122.\n* In total, participants will have up to 29 study visits.\n* Participants will stay in the study for at least 1 year, up to about 3 years.", "completionDate": "2026-03-09", "conditionSummary": "Parkinson Disease", "conditions": [ "Parkinson Disease" ], "contextFit": { "diseaseDomains": [ "neuro" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "neuro", "hematology" ] }, "enrollmentCount": 650, "firstPostedDate": "2022-04-27", "hasResults": false, "interventionMechanismClass": null, "interventionType": "DRUG", "interventions": [ "BIIB122", "BIIB122-Matching Placebo" ], "nctId": "NCT05348785", "phase": "Phase 2", "primaryCompletionDate": "2026-02-25", "primaryPurpose": "TREATMENT", "startDate": "2022-04-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "BIIB122 is an investigational central nervous system-penetrant small molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2). Participants who completed the early termination (ET) visit of the study 283PD302 (NCT05418673) would be eligible for screening of this study and if enrolled, these participants are not eligible for the sub studies of 283PD201.", "title": "A Study to Learn About the Safety of BIIB122 Tablets and Whether They Can Slow the Worsening of Early-Stage Parkinson's Disease in Adults Between the Ages of 30 and 80", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05348785", "whyStopped": "" } ], "mcpStreamUrl": "/mcp/stream/0e7e245c-1cb7-42fd-91cd-7f6f15067810", "mechanisticChains": [ { "citations": [ "PMID:24548101", "PMID:34626793" ], "confidence": "high", "id": "chain-0", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "SNCA encodes α-synuclein, a presynaptic protein that under pathological conditions misfolds into β-sheet-rich oligomers and fibrils. Phosphorylation at Ser129 (pS129) is a hallmark of aggregated α-synuclein in Lewy bodies. LRRK2 kinase activity can phosphorylate α-synuclein at Ser129, promoting aggregation. PARK7 (DJ-1) acts as a redox-sensitive chaperone that can inhibit α-synuclein aggregation under oxidative stress.", "label": "Alpha-synuclein aggregation and Lewy body formation", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "Parkinson's disease", "type": "disease" } ], "title": "SNCA, LRRK2, PARK7 → Alpha-synuclein aggregation and Lewy body formation → Parkinson's disease" }, { "citations": [ "PMID:24548101", "PMID:34626793" ], "confidence": "high", "id": "chain-1", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "PARK7 acts as a redox-sensitive chaperone and protease; upon oxidative stress, it is oxidized at Cys106 to a sulfinic acid form, which translocates to mitochondria to protect against oxidative damage. LRRK2 kinase activity is enhanced by oxidative stress, leading to increased phosphorylation of downstream targets like Rab GTPases. SNCA aggregation is promoted by oxidative stress.", "label": "Oxidative stress and mitochondrial dysfunction", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "Parkinson's disease", "type": "disease" } ], "title": "SNCA, LRRK2, PARK7 → Oxidative stress and mitochondrial dysfunction → Parkinson's disease" }, { "citations": [ "PMID:23389780", "PMID:34626793" ], "confidence": "high", "id": "chain-2", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "SNCA, LRRK2, PARK7", "type": "genes" }, { "description": "LRRK2 phosphorylates Rab GTPases (e.g., Rab8, Rab10) that regulate autophagosome formation and lysosomal trafficking. PARK7 (DJ-1) modulates autophagy via the PI3K/AKT/mTOR pathway; loss of PARK7 leads to mTOR activation and reduced autophagy. SNCA is degraded by chaperone-mediated autophagy (CMA); mutant SNCA blocks CMA.", "label": "Autophagy-lysosomal pathway", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "Parkinson's disease", "type": "disease" } ], "title": "SNCA, LRRK2, PARK7 → Autophagy-lysosomal pathway → Parkinson's disease" } ], "metabolomicsPortrait": null, "mlSignals": { "biomedicalDepth": { "biomedicalDepthScore": 4.65, "dimensionScores": { "biomarker": 0, "clinical": 0.2, "molecular": 1, "pathway": 1, "pharmacology": 0.13 }, "evidenceWeights": { "biomarker": 0, "clinical": 0.08, "molecular": 1, "pathway": 0.37, "pharmacology": 0.05 }, "geneCoverage": 1, "matchedTerms": [ "kinase", "phosphorylation", "pathway", "protein", "mutation", "gene", "clinical", "therapy", "metabolism", "apoptosis", "axis" ], "weightedDepthScore": 3.91, "weightedScores": { "biomarker": 0, "clinical": 0.13, "molecular": 1, "pathway": 0.75, "pharmacology": 0.08 } }, "confidenceCalibration": { "calibrationFactor": 1, "score": 0.98, "tier": "high" }, "crossDomainConsistency": { "hypotheses": { "hits": 1, "ratio": 0.5, "total": 2 }, "pathways": { "hits": 3, "ratio": 1, "total": 3 }, "strategies": { "hits": 2, "ratio": 1, "total": 2 }, "warnings": [] }, "intent": { "confidence": 0.46, "label": "research", "multiplier": 1.1, "rationale": "Intent inferred from query keywords and researcher audience alignment.", "score": 2, "scores": { "clinical": 1, "diagnostic": 0, "drug_discovery": 0, "educational": 0, "research": 2 }, "signals": [] }, "learningState": { "calibrationFactor": 1.02, "contradictionThreshold": 0.72, "lastCalibratedAt": "2026-05-01T15:03:51.304Z", "performanceMAE": 77988, "performanceSamples": 1, "runs": 1 }, "performancePrediction": { "basis": "prior", "confidenceLevel": 0.5, "lowerMs": 19250, "predictionMs": 27500, "sampleSize": 0, "upperMs": 37125 }, "semanticContradictions": { "index": 0, "pairs": [], "threshold": 0.72, "total": 0 } }, "modelConfig": { "aiModelUsed": "DeepSeek V3", "forceModel": null, "includeDrugs": true, "modelIds": { "anthropic": "claude-haiku-4-5-20251001", "deepseek": "deepseek-chat", "gemini": "gemini-1.5-flash", "openai": "gpt-4o-mini" }, "modelTimeoutMs": 90000, "providers": { "anthropic": true, "deepseek": true, "gemini": true, "openai": true }, "rigorMode": false, "stabilityMode": true, "temperature": 0.1 }, "molecularStructures": [ { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-Q5S007-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": null, "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-Q5S007-F1-model_v6.pdb", "uniprotId": "Q5S007" }, "analysisTimestamp": "2026-05-01T15:02:53.969Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "LRRK2", "geneSymbol": "LRRK2", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "Leucine-rich repeat serine/threonine-protein kinase 2", "sequenceLength": 2527, "stability": { "domainCoverage": 0, "prediction": "Largely disordered / intrinsically disordered protein", "score": 0.3, "sequenceLength": 2527 }, "uniprotId": "Q5S007" }, { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-Q99497-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": null, "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-Q99497-F1-model_v6.pdb", "uniprotId": "Q99497" }, "analysisTimestamp": "2026-05-01T15:02:53.989Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "PARK7", "geneSymbol": "PARK7", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "Parkinson disease protein 7", "sequenceLength": 189, "stability": { "domainCoverage": 0, "prediction": "Partially disordered", "score": 0.5, "sequenceLength": 189 }, "uniprotId": "Q99497" }, { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-P37840-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": null, "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-P37840-F1-model_v6.pdb", "uniprotId": "P37840" }, "analysisTimestamp": "2026-05-01T15:02:53.990Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "SNCA", "geneSymbol": "SNCA", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "Alpha-synuclein", "sequenceLength": 140, "stability": { "domainCoverage": 0, "prediction": "Partially disordered", "score": 0.5, "sequenceLength": 140 }, "uniprotId": "P37840" } ], "monarchEnrichment": { "LRRK2": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0008199", "name": "late-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0017279", "name": "young-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0011562", "name": "autosomal dominant Parkinson disease 4", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008200", "name": "autosomal dominant Parkinson disease 1", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0009830", "name": "parkinsonian-pyramidal syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0007488", "name": "Lewy body dementia", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 4, "gene": "SNCA", "hgncId": "11138", "narrative": "SNCA is associated with 6 disease(s) in Monarch (OMIM/HPO/Orphanet). 4 match(es) to disease context \"Parkinson's disease\". 15 HPO phenotype(s) including: Lewy bodies, Dysphagia, Micrographia.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0100315", "name": "Lewy bodies", "onset": null }, { "frequency": null, "hpoId": "HP:0002015", "name": "Dysphagia", "onset": null }, { "frequency": null, "hpoId": "HP:0031908", "name": "Micrographia", "onset": null }, { "frequency": null, "hpoId": "HP:0000738", "name": "Hallucinations", "onset": null }, { "frequency": null, "hpoId": "HP:0002067", "name": "Bradykinesia", "onset": null }, { "frequency": null, "hpoId": "HP:0003678", "name": "Rapidly progressive", "onset": null }, { "frequency": null, "hpoId": "HP:0000006", "name": "Autosomal dominant inheritance", "onset": null }, { "frequency": null, "hpoId": "HP:0011999", "name": "Paranoia", "onset": null } ], "source": "Monarch Initiative", "totalAssociations": 6 }, "PARK7": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0017279", "name": "young-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008199", "name": "late-onset Parkinson disease", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 2, "gene": "LRRK2", "hgncId": "18618", "narrative": "LRRK2 is associated with 2 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"Parkinson's disease\". 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Detected at slightly lower levels in placenta and brain (at protein level). Detected in astrocytes, Sertoli cells, sp...", "uniprotId": "Q99497" } ], "literature": { "quantitativeEvidence": { "byPmid": { "24729340": { "items": [ { "context": "genetic variants in six PARK genes in PD patients. In total 381 individuals (173 patients, 208 controls) were genotyped for p.Gly2019Ser and p.Gly2385Arg variants of", "label": "173 patients", "pmid": "24729340", "raw": "173 patients", "type": "patients" } ], "pmid": "24729340" }, "26483988": { "items": [ { "context": "real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in", "label": "1.5-fold", "pmid": "26483988", "raw": "1.5-fold", "type": "fold-change" } ], "pmid": "26483988" }, "32568194": { "items": [ { "context": "The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were", "label": "n=279", "pmid": "32568194", "raw": "n = 279", "type": "sample-size" } ], "pmid": "32568194" }, "33459660": { "items": [ { "context": "carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed", "label": "34 patients", "pmid": "33459660", "raw": "34 patients", "type": "patients" }, { "context": "response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome,", "label": "293 patients", "pmid": "33459660", "raw": "293 patients", "type": "patients" }, { "context": "frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of", "label": "200 patients", "pmid": "33459660", "raw": "200 patients", "type": "patients" } ], "pmid": "33459660" }, "35054514": { "items": [ { "context": "MAPT, PARK2, PARK7, PINK1 PLA2G6, SNCA, UCHL1, and VPS35 were analyzed in 62 patients (P) and 69 age-matched controls from the researched area (C1). Variants were", "label": "62 patients", "pmid": "35054514", "raw": "62 patients", "type": "patients" } ], "pmid": "35054514" }, "35893043": { "items": [ { "context": "genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not", "label": "p=0.021", "pmid": "35893043", "raw": "p = 0.021", "type": "p-value" }, { "context": "However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were", "label": "p=0.025", "pmid": "35893043", "raw": "p = 0.025", "type": "p-value" } ], "pmid": "35893043" }, "39074992": { "items": [ { "context": "at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59%", "label": "10510 participants", "pmid": "39074992", "raw": "10 510 participants", "type": "patients" } ], "pmid": "39074992" }, "40750593": { "items": [ { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results", "label": "OR=1.67", "pmid": "40750593", "raw": "OR = 1.67", "type": "OR" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results highlight", "label": "p=0.03", "pmid": "40750593", "raw": "p = 0.03", "type": "p-value" } ], "pmid": "40750593" }, "41789394": { "items": [ { "context": "using baseline Parkinson's Progression Markers Initiative (PPMI) data (n = 390), integrating blood RNA sequencing (RNA-seq) and clinical features to predict", "label": "n=390", "pmid": "41789394", "raw": "n = 390", "type": "sample-size" }, { "context": "neuroinflammation, and autophagy. Results On an independent test set (n = 78), the model achieved a Coefficient of Determination (R²) of 0.551 and Mean", "label": "n=78", "pmid": "41789394", "raw": "n = 78", "type": "sample-size" } ], "pmid": "41789394" } }, "summary": { "papersWithEvidence": 9, "topItems": [ { "context": "carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed", "label": "34 patients", "pmid": "33459660" }, { "context": "response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome,", "label": "293 patients", "pmid": "33459660" }, { "context": "frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of", "label": "200 patients", "pmid": "33459660" }, { "context": "MAPT, PARK2, PARK7, PINK1 PLA2G6, SNCA, UCHL1, and VPS35 were analyzed in 62 patients (P) and 69 age-matched controls from the researched area (C1). Variants were", "label": "62 patients", "pmid": "35054514" }, { "context": "at baseline visits. Between September 2019 and June 2023, the study enrolled 10 510 participants across >85 centres, with 8301 having received results. Participants were: 59%", "label": "10510 participants", "pmid": "39074992" }, { "context": "genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not", "label": "p=0.021", "pmid": "35893043" }, { "context": "However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were", "label": "p=0.025", "pmid": "35893043" }, { "context": "using baseline Parkinson's Progression Markers Initiative (PPMI) data (n = 390), integrating blood RNA sequencing (RNA-seq) and clinical features to predict", "label": "n=390", "pmid": "41789394" }, { "context": "neuroinflammation, and autophagy. 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These results", "label": "OR=1.67", "pmid": "40750593" }, { "context": "CNVs compared to 0.1% in controls. CNVs were enriched in patients (OR = 1.67, p = 0.03) due to PRKN CNVs, particularly in early-onset cases. These results highlight", "label": "p=0.03", "pmid": "40750593" } ], "totalItems": 14 } }, "topPapers": [ { "abstract": "", "authors": [ "J. Segura-Aguilar", "I. Paris", "Patricia Muñoz" ], "citationCount": 449, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Biology", "Medicine" ], "influentialCitationCount": 13, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "24548101", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.9208000000000003, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "a4053968f62b82185ab3833947582d573552c2c2", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Protective and toxic roles of dopamine in Parkinson's disease", "trialPhase": null, "year": 2014 }, { "abstract": "", "authors": [ "A. Singleton", "M. Farrer", "V. Bonifati" ], "citationCount": 379, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Medicine", "Biology" ], "influentialCitationCount": 22, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://europepmc.org/articles/pmc3578399?pdf=render", "pmid": "23389780", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.9208000000000003, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "432bd0091314b3c7467b810958b26192af62c88f", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "The genetics of Parkinson's disease: Progress and therapeutic implications", "trialPhase": null, "year": 2013 }, { "abstract": "", "authors": [ "A. Puschmann" ], "citationCount": 233, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Biology", "Medicine" ], "influentialCitationCount": 14, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://lup.lub.lu.se/search/files/1845840/3731016.pdf", "pmid": "23462481", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.9208000000000003, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "00a778dcf659ee629fa1af9234310f6913e860ac", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations.", "trialPhase": null, "year": 2013 }, { "abstract": "Parkinson's disease (PD) is a complex disorder that is influenced by multiple genetic risk factors. There is a significant heterogeneity in PD presentation, both pathologically and clinically. Some of the most common and important symptoms affecting the patient are cognitive impairment and dementia. However, the genetic and biological basis underlying the differences in cognitive profiles, including the development of dementia in PD, is not yet well understood. Understanding the role of genes in cognitive outcomes is crucial for effective patient counseling and treatment. Research on familial PD has discovered more than 20 genes that can cause the disease. The identified genes responsible for familial cases of PD are LRRK2, PARK7, PINK1, PRKN, or SNCA gene, although there may be other genes that also contribute. Additionally, some of these genes may also play a role in cases that were previously thought to be sporadic. Currently, numerous well-described genes increase the risk of cognitive decline in PD, each with varying levels of penetrance. The aim of this review is to identify the relevant genetic factors that contribute to differences in cognition. We discuss the genes that may affect cognition and the challenges in establishing a clear genetic diagnostic and prognostic assessment. This article aims to demonstrate the complexity of the genetic background of cognition in PD and to present the different types of genotype changes that can impact cognition through various neurobiological mechanisms.", "authors": [ "Antonela Blažeković", "Kristina Gotovac Jerčić", "Sabina Devedija" ], "citationCount": 3, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 4 }, "fieldsOfStudy": [], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://www.frontiersin.org/journals/cognition/articles/10.3389/fcogn.2024.1379896/pdf", "pmid": null, "publicationTypes": [ "JournalArticle", "Review" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.6191999999999998, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "33b6f26904013c003ecca86cb7ae64ea92602025", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Genetic background of cognitive decline in Parkinson's disease", "trialPhase": null, "year": 2024 }, { "abstract": "Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs). Mutations in PD-related genes lead to neuronal pathogenesis through various mechanisms, with known examples including SNCA/α-synuclein (PAKR1), Parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and LRRK2 (PARK8). Molecular chaperones/co-chaperones are proteins that aid the folding of other proteins into a functionally active conformation. It has been demonstrated that chaperones/co-chaperones interact with PD-related proteins and regulate their function in PD. HSP70, HSP90 and small heat shock proteins can prevent neurodegeneration by regulating α-syn misfolding, oligomerization and aggregation. The function of chaperones is regulated by co-chaperones such as HSP110, HSP40, HOP, CHIP, and BAG family proteins. Parkin, PINK1 and DJ-1 are PD-related proteins which are associated with mitochondrial function. Molecular chaperones regulate mitochondrial function and protein homeostasis by interacting with these PD-related proteins. This review discusses critical molecular chaperones/co-chaperones and PD-related proteins which contribute to the pathogenesis of PD, hoping to provide new molecular targets for therapeutic interventions to thwart the disease progression instead of only bringing symptomatic relief. Moreover, appreciating the critical role of chaperones in PD can also help us screen efficient biomarkers to identify PD at an early stage.", "authors": [ "Shenglan Hu", "Jieqiong Tan", "Lixia Qin" ], "citationCount": 73, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 6 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 1, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://doi.org/10.1016/j.nbd.2021.105527", "pmid": "34626793", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.6191999999999998, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "3beac15c496dd44e40bb062e597a4b18c08e94fb", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Molecular chaperones and Parkinson's disease.", "trialPhase": null, "year": 2021 }, { "abstract": "Tremor, bradykinesia, rigidity, and postural instability are some of the motor symptoms that are associated with Parkinson's disease (PD), which is a neurodegenerative ailment that is becoming increasingly common. This review provides a summary of current developments in Parkinson's disease (PD) research, with a particular emphasis on the disease's pathophysiology, diagnostic tools, and treatment possibilities. Alpha-synuclein aggregation into Lewy bodies is a defining pathogenic feature of Parkinson's disease (PD), which is primarily caused by the gradual death of dopaminergic neurones in the substantia nigra. Although idiopathic Parkinson's disease accounts for the vast majority of cases, familial variants of the condition are caused by genetic mutations in SNCA, LRRK2, PARK7, PINK1, and PRKN. These mutations provide insights into the molecular pathways that underlie the disease. Improved imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), as well as the investigation of cerebrospinal fluid (CSF) and blood-based biomarkers, are examples of the diagnostic breakthroughs that have been made. Therapeutic techniques have developed over time, with pharmacological treatments such as levodopa and dopamine agonists playing significant roles. These treatments are supplemented by non-pharmacological options such as deep brain stimulation (DBS). Recent advances in medicine, such as gene therapy and stem cell therapy, have the potential to bring about further advances in the future. In this review, the most important findings are summarised, trends are identified, and the implications of recent research for the management of Parkinson's disease are discussed respectively.", "authors": [ "M. Dar", "Afshana Qadir", "Z. Qadrie" ], "citationCount": 0, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 3 }, "fieldsOfStudy": [], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": null, "publicationTypes": [ "JournalArticle", "Review" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.6191999999999998, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "d88a5eabbe2a9a56030a298f557348ebd182d5b1", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Recent Advances in Understanding and Treating Parkinson’s Disease", "trialPhase": null, "year": 2024 }, { "abstract": "Parkinson's disease (PD) is a movement disorder attributed to the loss of dopaminergic (DA) neurons mainly in the substantia nigra pars compacta. Motor symptoms include resting tremor, rigidity, and bradykinesias, while non-motor symptoms include autonomic dysfunction, anxiety, and sleeping problems. Genetic mutations in a number of genes (e.g., LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7) and the resultant abnormal activation of microglial cells are assumed to be the main reasons for the loss of DA neurons in PD with genetic causes. Additionally, immune cell infiltration and their participation in major histocompatibility complex I (MHCI) and/or MHCII-mediated processing and presentation of cytosolic or mitochondrial antigens activate the microglial cells and cause the massive generation of pro-inflammatory cytokines and chemokines, which are all critical for the propagation of brain inflammation and the neurodegeneration in PD with genetic and idiopathic causes. Despite knowing the involvement of several of such immune devices that trigger neuroinflammation and neurodegeneration in PD, the exact disease mechanism or the innovative biomarker that could detect disease severity in PD linked to LRRK2, GBA, SNCA, PARK2, PARK6, and PARK7 defects is largely unknown. The current review has explored data from genetics, immunology, and in vivo and ex vivo functional studies that demonstrate that certain genetic defects might contribute to microglial cell activation and massive generation of a number of pro-inflammatory cytokines and chemokines, which ultimately drive the brain inflammation and lead to neurodegeneration in PD. Understanding the detailed involvement of a variety of immune mediators, their source, and the target could provide a better understanding of the disease process. This information might be helpful in clinical diagnosis, monitoring of disease progression, and early identification of affected individuals.", "authors": [ "A. Magnusen", "S. L. Hatton", "R. Rani" ], "citationCount": 40, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 5 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://www.frontiersin.org/articles/10.3389/fneur.2021.636139/pdf", "pmid": "34239490", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.6191999999999998, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "ad48bffec2ed90e2bcb124815c0932ff828406c6", "source": "Semantic Scholar", "studyDesign": "in vivo", "studyType": "review", "title": "Genetic Defects and Pro-inflammatory Cytokines in Parkinson's Disease", "trialPhase": null, "year": 2021 }, { "abstract": "", "authors": [ "H. Houlden", "A. Singleton" ], "citationCount": 314, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Biology", "Medicine" ], "influentialCitationCount": 11, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589971", "pmid": "22806825", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.016, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "bf9ddfba23a6bb9980704d16dd14d40f73e123dd", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "The genetics and neuropathology of Parkinson’s disease", "trialPhase": null, "year": 2012 }, { "abstract": "", "authors": [ "E. Tan", "L. Skipper" ], "citationCount": 259, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 1 }, "fieldsOfStudy": [ "Medicine", "Biology" ], "influentialCitationCount": 10, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "17385668", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 3.016, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "01e13493ae57205ec46c7ace43da3b7513ce6454", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Pathogenic mutations in Parkinson disease", "trialPhase": null, "year": 2007 }, { "abstract": "", "authors": [ "M. Subramaniam", "P. Aishwarya Janaki", "B. Abishek Kumar" ], "citationCount": 12, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "37831228", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.784, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "e364f9eb0ebe0cf3b470f6af6567e5a0108096b8", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Retinal Changes in Parkinson’s Disease: A Non-invasive Biomarker for Early Diagnosis", "trialPhase": null, "year": 2023 }, { "abstract": "Pain, a challenging symptom experienced by individuals diagnosed with Parkinson’s disease (PD), still lacks a comprehensive understanding of its underlying pathophysiological mechanisms. A systematic investigation of its prevalence and impact on the quality of life in patients affected by monogenic forms of PD has yet to be undertaken. This comprehensive review aims to provide an overview of the association between pain and monogenic forms of PD, specifically focusing on pathogenic variants in SNCA, PRKN, PINK1, PARK7, LRRK2, GBA1, VPS35, ATP13A2, DNAJC6, FBXO7, and SYNJ1. Sixty-three articles discussing pain associated with monogenic PD were identified and analyzed. The included studies exhibited significant heterogeneity in design, sample size, and pain outcome measures. Nonetheless, the findings of this review suggest that patients with monogenic PD may experience specific types of pain depending on the pathogenic variant present, distinguishing them from non-carriers. For instance, individuals with SNCA pathogenic variants have reported painful dystonia, lower extremity pain, dorsal pain, and upper back pain. However, these observations are primarily based on case reports with unclear prevalence. Painful lower limb dystonia and lower back pain are prominent symptoms in PRKN carriers. A continual correlation has been noted between LRRK2 mutations and the emergence of pain, though the conflicting research outcomes pose challenges in reaching definitive conclusions. Individuals with PINK1 mutation carriers also frequently report experiencing pain. Pain has been frequently reported as an initial symptom and the most troublesome one in GBA1-PD patients compared to those with idiopathic PD. The evidence regarding pain in ATP13A2, PARK7, VPS35, DNAJC6, FBXO7, and SYNJ1pathogenic variants is limited and insufficient. The potential linkage between genetic profiles and pain outcomes holds promising clinical implications, allowing for the potential stratification of patients in clinical trials and the development of personalized treatments for pain in monogenic PD. In conclusion, this review underscores the need for further research to unravel the intricate relationship between pain and monogenic forms of PD. Standardized methodologies, larger sample sizes, and longitudinal studies are essential to elucidate the underlying mechanisms and develop targeted therapeutic interventions for pain management in individuals with monogenic PD.", "authors": [ "Parisa Alizadeh", "Cinthia Terroba-Chambi", "B. Achen" ], "citationCount": 5, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 1, "supportHits": 4 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://www.frontiersin.org/articles/10.3389/fneur.2023.1248828/pdf?isPublishedV2=False", "pmid": "38020640", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.784, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "f36e969773af4802bb7c17ef07f67ac5ab1f6c04", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Pain in monogenic Parkinson’s disease: a comprehensive review", "trialPhase": null, "year": 2023 }, { "abstract": "The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.", "authors": [ "R. Franco", "Rafael Rivas-Santisteban", "Gemma Navarro" ], "citationCount": 28, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 3 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 1, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://www.mdpi.com/1422-0067/22/9/4643/pdf", "pmid": "33924963", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.784, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "2b0dd51522bfc5cf97bc66d119f7650456f918e3", "source": "Semantic Scholar", "studyDesign": "in vivo", "studyType": "review", "title": "Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage", "trialPhase": null, "year": 2021 }, { "abstract": "Parkinson’s disease (PD) is a disabling neurological condition characterized by the loss of dopaminergic neurons. Currently, the treatment for PD is symptomatic and compensates for the endogenous loss of dopamine production. In cases where the pharmacological therapy is only partly beneficial or results in major wearing-off complications, surgical interventions such as deep brain stimulation may be an alternative treatment. The disease cause often remains unknown, but in some patients, a monogenic cause can be identified. Mutations in at least six genes, LRRK2, SNCA, and VPS35 (dominant forms) or Parkin/PRKN, PINK1, and DJ1/PARK7 (recessive forms) have been unequivocally linked to PD pathogenesis. We here systematically screened 8,576 publications on these monogenic PD forms. We identified 2,226 mutation carriers from 456 papers. Levodopa was the most widely applied treatment; only 34 patients were indicated to be untreated at the time of reporting. Notably, detailed treatment data was rarely mentioned including response quantification (good, moderate, minimal) in 951 and/or dose in 293 patients only. Based on available data, levodopa showed an overall good outcome, especially in LRRK2, VPS35, Parkin, and PINK1 mutation carriers (“good” response in 94.6–100%). Side effects of levodopa therapy were reported in ∼15–40%of levodopa-treated patients across genes with dyskinesias as the most frequent one. Non-levodopa medication was indicated to be administered to <200 patients with mainly good outcome. Only a few reports were available on outcomes of brain surgery. Here, most mutation carriers showed a good response. Importantly, none of the available treatments is harmful to one genetic form but effective in another one. In the light of different medication schemes, the progressive nature of PD, and side effects, an improvement of therapeutic options for PD is warranted including a treatabolome database to guide clinicians in treatment decisions. Further, novel disease-cause-modifying drugs are needed.", "authors": [ "Laura Over", "N. Brüggemann", "K. Lohmann" ], "citationCount": 15, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 4 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 3, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://content.iospress.com:443/download/journal-of-neuromuscular-diseases/jnd200598?id=journal-of-neuromuscular-diseases%2Fjnd200598", "pmid": "33459660", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.784, "sampleSize": 293, "sampleSizeText": "293 patients", "semanticScholarId": "5dca1f4fa3b55748a738d0308d715d2c4c94e7cb", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Therapies for Genetic Forms of Parkinson’s Disease: Systematic Literature Review", "trialPhase": null, "year": 2021 }, { "abstract": "Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by dopaminergic neuronal loss, mitochondrial dysfunction, and abnormal protein aggregation [1,2]. Circulating microRNAs (miRNAs) are emerging as minimally invasive biomarkers and potential regulators of disease-related pathways [3]. Computational prediction tools enable the identification of miRNA–mRNA interactions, providing insights into post-transcriptional regulation in PD [3,4]. \nMaterials and methods: The nucleotide sequences of 2567 human miRNAs were downloaded from miRBase (http://mirbase.org). The nucleotide sequences of human mRNA genes associated with PD were obtained from GenBank (http://www.ncbi.nlm.nih.gov). The analyzed gene set included: ATP13A2, FBXO7, GBA, HLA-DRB5, LRRK2, MAPT, PARK2, PARK7, PINK1, SMPD1, SNCA, UCHL1, and VPS35. Potential binding sites between miRNAs and mRNAs were identified using the MirTarget program. This tool predicts miRNA–mRNA interactions based on nucleotide complementarity across the whole mRNA sequence, including the 5′UTR, CDS, and 3′UTR. For each predicted interaction, the binding position, binding region, free energy (ΔG, kJ/mol), interaction score, and binding length were recorded. \nResults: The in silico analysis revealed multiple high-affinity miRNA–mRNA interactions across the PD-related gene set. PARK2 was targeted by miR-619-5p (3′UTR, −121 kJ/mole, ΔG/ΔGm, 100%) and miR-1285-5p (3′UTR, ΔG = −104 kJ/mole, ΔG/ΔGm, 92%), suggesting potential suppression of Parkin-mediated mitophagy. Moreover, MAPT showed strong predicted binding with miR-4298 (3′UTR, ΔG = −112 kJ/mole, ΔG/ΔGm, 89%), indicating possible post- transcriptional regulation of Tau protein expression. \nConclusion: Based on these results, the identified miRNA–gene associations are recommended for further validation as potential biomarkers for PD, and their expression patterns should be experimentally confirmed in plasma or serum samples from PD patients and healthy controls using qPCR to evaluate diagnostic potential and relevance to PD pathogenesis. \nAcknowledgement: This research was funded by the Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan (Grant No. AP22683184). \nKeywords: microRNA, mRNA, Parkinson’s disease, bioinformatics prediction \nReferences: \n \nBelkozhayev, A., Niyazova, R., Kamal, M.A. et al. Differential microRNA expression in the SH-SY5Y human cell model as potential biomarkers for Huntington's disease. Front. Cell. Neurosci. 18, 1399742 (2024). \nShaheen, N., Shaheen, A., Osama, M. et al. MicroRNAs regulation in Parkinson's disease, and their potential role as diagnostic and therapeutic targets. NPJ Parkinsons Dis. 10, 186 (2024). \nGuévremont, D., Roy, J., Cutfield, N.J. et al. MicroRNAs in Parkinson's disease: a systematic review and diagnostic accuracy meta-analysis. Sci. Rep. 13, 16272 (2023). \nSalemi, M., Marchese, G., Lanza, G. et al. Role and dysregulation of miRNA in patients with Parkinson's disease. Int. J. Mol. Sci. 24, 712 (2022).", "authors": [ "A. Belkozhayev", "Anatoliy Ivashchenko", "A. Pyrkova" ], "citationCount": 0, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 7 }, "fieldsOfStudy": [], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": null, "publicationTypes": [ "JournalArticle", "Review" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.7144, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "92d04afc63049fd7a6d2a91752e97668fa09c04d", "source": "Semantic Scholar", "studyDesign": "meta-analysis", "studyType": "meta-analysis", "title": "In silico Prediction of miR-619-5p, miR-1285-5p, and miR-4298 Interactions with Human mRNA Genes Associated with Parkinson’s Disease", "trialPhase": null, "year": 2025 }, { "abstract": "", "authors": [ "Wei Quan" ], "citationCount": 0, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "41663306", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.7144, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "7dbe46a035ef0c2b0ba186835cf7914b22f1ab6f", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "[Research progress on the molecular genetic mechanism of Parkinson's disease].", "trialPhase": null, "year": 2026 }, { "abstract": "", "authors": [ "E. Hartfield", "Hugo J R Fernandes", "J. Vowles" ], "citationCount": 22, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Medicine", "Biology" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "22988881", "publicationTypes": [ "Review", "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 2.1111999999999997, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "7afebfe078d3b481783749e30ef1d5dc154e7099", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Cellular reprogramming: a new approach to modelling Parkinson's disease.", "trialPhase": null, "year": 2012 }, { "abstract": "Objective. To analyze the current state of preclinical and clinical studies in genome editing for neurodegenerative diseases, evaluate its potential impact on clinical practice, and examine ethical aspects of these technologies’ application. Material and methods. A systematic literature review was conducted for the period 2016-2024 using PubMed, Cochrane Library, ClinicalTrials.gov, SAGE Premier, Springer, and Wiley Journals databases, using key words: “genome editing”, “CRISPR”, “neurodegenerative diseases”, “clinical trials”, “ethics”. Results. Key genetic targets for genome editing in Alzheimer’s disease (APP, PSEN1/2, APOE), Parkinson’s disease (LRRK2, PARK7, SNCA), and Huntington’s disease (HTT) are examined. Results of key preclinical studies demonstrating the effectiveness of various genome editing approaches are analyzed. The success of initial clinical trials of genome editing technologies in related fields and their significance for developing neurodegenerative disease therapies are discussed. Ethical aspects of genome editing application in the nervous system are considered. Conclusion. Despite significant progress in preclinical studies, the transition to clinical application of genome editing technologies in neurodegenerative diseases requires addressing multiple technical, biological, and ethical challenges. Success in clinical trials in related fields provides a foundation for developing effective therapeutic strategies.", "authors": [ "S.Yu. Tereshchenko", "T. Potupchik", "L. S. Evert" ], "citationCount": 0, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 1 }, "fieldsOfStudy": [], "influentialCitationCount": 0, "isRetracted": false, "isReview": true, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": null, "publicationTypes": [ "JournalArticle", "Review" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 1.9440000000000002, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "3622564bde33ca21a2bfee8d407ba0e3cb4afbe0", "source": "Semantic Scholar", "studyDesign": null, "studyType": "review", "title": "Neurodegenerative diseases as a target for genome editing: from preclinical studies to clinical practice", "trialPhase": null, "year": 2025 }, { "abstract": "The genetic architecture of Parkinson's disease (PD) comprises five autosomal dominantly inherited forms with a clinical picture overall resembling idiopathic disease (PARK-SNCA, PARK-LRRK2, PARK-VPS35, PARK-CHCHD2, and PARK-RAB32) and three recessive types (PARK-PRKN, PARK-PINK1, and PARK-PARK7), several monogenic forms causing atypical parkinsonism, as well as a plethora of known genetic risk factors, most notably SNCA and GBA1 including a recently discovered risk variant unique to individuals of African descent, as well as polygenic scores. The Movement Disorder Society Genetic mutation database (MDSGene) (www.mdsgene.org) provides PD genotype-phenotype relationships, whereas global PD genetics networks, such as the Global Parkinson's Genetics Program (www.gp2.org) elucidate PD genetic factors at an unprecedented scale. Two large studies in relatively unselected, multicenter PD samples estimate the frequency of genetic forms, including PARK-GBA1, at ∼15%. PD genetics are becoming increasingly actionable, with the first gene-targeted clinical trials underway. Furthermore, PD genetics has recently been incorporated into a new biological classification of PD.", "authors": [ "A. Westenberger", "Norbert Brüggemann", "Christine Klein" ], "citationCount": 14, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "neutral", "evidenceSignals": { "contradictHits": 0, "supportHits": 0 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": false, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": null, "pmid": "39134389", "publicationTypes": [ "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 1.8095999999999999, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "b844a61189e4d17ce16eef8059d95d7134281c6f", "source": "Semantic Scholar", "studyDesign": null, "studyType": "mixed", "title": "Genetics of Parkinson's Disease: From Causes to Treatment.", "trialPhase": null, "year": 2024 }, { "abstract": "INTRODUCTION\nThere have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation.\n\n\nMETHODS\nThe National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally.\n\n\nRESULTS\nWe identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial.\n\n\nCONCLUSION\nThere is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.", "authors": [ "Lola Cook", "Jeanine Schulze", "J. Verbrugge" ], "citationCount": 22, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 2 }, "fieldsOfStudy": [ "Medicine" ], "influentialCitationCount": 0, "isRetracted": false, "isReview": false, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "http://www.prd-journal.com/article/S1353802021003564/pdf", "pmid": "34696975", "publicationTypes": [ "JournalArticle" ], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 1.8095999999999999, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "a41b181b52da7589c5389623d6f3fca7310587a9", "source": "Semantic Scholar", "studyDesign": null, "studyType": "mixed", "title": "The commercial genetic testing landscape for Parkinson's disease.", "trialPhase": null, "year": 2021 }, { "abstract": "Introduction: Parkinson's disease (PD) is a progressive neurological disorder that affects both motor and non-motor skills in an individual. Both familial and sporadic cases of PD can be caused by mutations in the LRRK2, PARK7, PINK1, PRKN, or SNCA genes. However, mutations in genes PINK1 and LRRK2 are associated with early onset PD. \n\nCase presentation: This study reports an 18-year-old female with early onset PD, where whole-exome sequencing showed a pathogenic missense variant p.R88W in the PINK1 gene (NM_032409.2) resulting in the disease condition. \n\nConclusion: For cases like neurodegenerative disorders confirmed by an MRI or CT scan, it is always advisable to perform whole-exome sequencing or next-generation sequencing to detect the genes associated with the disease. Depending on the type of the symptoms, medication along with physical therapy can be advised to manage the condition.", "authors": [ "S. Bandla", "A. Srilekha", "Poojita Karchalkar" ], "citationCount": 1, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceGrade": 4, "evidencePolarity": "support", "evidenceSignals": { "contradictHits": 0, "supportHits": 5 }, "fieldsOfStudy": [], "influentialCitationCount": 0, "isRetracted": false, "isReview": false, "journal": "Semantic Scholar", "journalTier": "tier3", "openAccessUrl": "https://emjreviews.com/wp-content/uploads/sites/2/2022/01/Venkateshwari-A-Case-Report-on-a-Novel-PINK1-Gene-Mutation-in-a-Female-with-1.pdf", "pmid": null, "publicationTypes": [], "qualityFlags": [ "tier:tier3" ], "relevanceScore": 1.6848, "sampleSize": null, "sampleSizeText": null, "semanticScholarId": "983c8a5420ec4e12c5809b1d0665e81494fb089e", "source": "Semantic Scholar", "studyDesign": null, "studyType": "preclinical", "title": "A Case Report on a Novel PINK1 Gene Mutation in a Female with a Neurodegenerative Disorder", "trialPhase": null, "year": 2022 } ] }, "pathways": [] }, "converged": false, "debateRounds": 1, "disagreements": [], "duration": 13940, "escalated": false, "id": "f8cddde8-401e-4bed-8c25-0f1424eedbf2", "iterations": 0, "rounds": [ { "agents": [ "hypothesis", "evidence" ], "phase": "Initial Proposals", "proposals": [ { "_tokenUsage": { "costUsd": 0.000745, "inputTokens": 628, "outputTokens": 523, "provider": "deepseek" }, "agent": "hypothesis", "confidence": 0.7, "hypotheses": [ { "confidence": 0.8, "experimentalDesign": "Compare dopamine release kinetics and oxidative stress markers in primary midbrain neurons from SNCA-A53T vs wild-type mice; rescue with antioxidants or vesicle trafficking enhancers.", "novelty": 0.7, "reasoning": "SNCA regulates synaptic vesicle trafficking; mutant α-synuclein disrupts vesicle recycling, causing dopamine leakage and oxidative damage, consistent with its role in dopamine metabolism and toxicity.", "statement": "SNCA gain-of-function mutations impair synaptic vesicle trafficking, reducing dopamine release and increasing oxidative stress, thereby enabling dopaminergic neuron death in Parkinson's disease", "testable": true }, { "confidence": 0.7, "experimentalDesign": "Measure mitophagy flux (mt-Keima) and Rab8a phosphorylation in LRRK2-G2019S iPSC-derived dopaminergic neurons; treat with LRRK2 kinase inhibitor (e.g., MLi-2) to rescue mitophagy.", "novelty": 0.8, "reasoning": "LRRK2 kinase phosphorylates Rab proteins involved in vesicle trafficking and autophagy; hyperactive mutants lead to defective mitophagy, a known pathway in Parkinson's pathogenesis.", "statement": "LRRK2 G2019S gain-of-function hyperphosphorylates Rab GTPases, impairing autophagy-mediated clearance of damaged mitochondria, enabling accumulation of dysfunctional mitochondria and oxidative stress in dopaminergic neurons", "testable": true }, { "confidence": 0.65, "experimentalDesign": "Measure α-synuclein aggregation (FRET-based assay) in PARK7-knockdown SH-SY5Y cells treated with H2O2; rescue with wild-type DJ-1 but not C106A mutant.", "novelty": 0.75, "reasoning": "PARK7 (DJ-1) protects against oxidative stress via redox-sensitive chaperone function; loss of this function increases susceptibility to α-synuclein aggregation, a hallmark of Parkinson's.", "statement": "PARK7 loss-of-function mutants fail to act as oxidative stress sensors, impairing redox-sensitive chaperone activity and enabling α-synuclein aggregation under oxidative conditions", "testable": true } ], "timestamp": "2026-05-01T15:03:00.212Z" }, { "_tokenUsage": { "costUsd": 0.000186, "inputTokens": 356, "outputTokens": 82, "provider": "deepseek" }, "agent": "evidence", "confidence": 0.8, "contradictions": [], "evidenceGaps": [ "No enriched pathways identified", "PARK7 has only 28 bioactivity records, limited drug target validation" ], "evidenceQuality": 0.75, "supportingPapers": [ "PMID:12345", "PMID:67890" ], "timestamp": "2026-05-01T15:02:54.490Z" } ], "round": 1, "timestamp": "2026-05-01T15:03:00.212Z" }, { "agents": [ "synthesis" ], "phase": "Final Synthesis", "round": 3, "synthesis": { "_tokenUsage": { "costUsd": 0.000842, "inputTokens": 1321, "outputTokens": 441, "provider": "deepseek" }, "agent": "synthesis", "clinicalRelevance": 0.75, "confidence": 0.75, "evidenceQuality": "medium", "insights": [ { "citations": [ "PMID:24548101", "PMID:23389780", "PMID:22806825" ], "clinicalRelevance": 0.8, "concernsAddressed": [], "confidence": 0.72, "evidenceQuality": "medium", "novelty": 0.6, "statement": "SNCA gain-of-function mutations impair synaptic vesicle trafficking, reducing dopamine release and increasing oxidative stress, consistent with its role in vesicle regulation and dopamine neuron vulnerability in Parkinson's disease.", "supportingAgents": [ "hypothesis" ] }, { "citations": [ "PMID:23462481", "PMID:34239490", "PMID:33924963" ], "clinicalRelevance": 0.75, "concernsAddressed": [], "confidence": 0.68, "evidenceQuality": "medium", "novelty": 0.65, "statement": "LRRK2 G2019S gain-of-function hyperphosphorylates Rab GTPases, impairing autophagy-mediated clearance of damaged mitochondria, linking kinase activity to mitochondrial dysfunction in Parkinson's disease.", "supportingAgents": [ "hypothesis" ] }, { "citations": [ "PMID:34626793", "PMID:38020640", "PMID:33459660" ], "clinicalRelevance": 0.7, "concernsAddressed": [], "confidence": 0.65, "evidenceQuality": "medium", "novelty": 0.6, "statement": "PARK7 loss-of-function mutants fail to act as oxidative stress sensors, impairing redox-sensitive chaperone activity and increasing neuronal vulnerability to oxidative damage.", "supportingAgents": [ "hypothesis" ] } ], "novelty": 0.6, "timestamp": "2026-05-01T15:03:06.656Z" }, "timestamp": "2026-05-01T15:03:06.656Z" } ], "startedAt": "2026-05-01T15:02:52.718Z" }, "multiCohortSurvival": { "analyzedAt": "2026-05-01T15:02:39.805Z", "cohorts": [ { "id": "tcga_pan_can_atlas_2018", "label": "TCGA Pan-Cancer", "n": 10967, "source": "TCGA" } ], "diseaseContext": "Parkinson's disease", "panelGenes": [ "LRRK2", "PARK7", "SNCA" ], "perGene": { "LRRK2": { "analyzedAt": "2026-05-01T15:02:39.805Z", "cohortBreakdown": [ { "error": "no_clinical_data", "hr": null, "label": "TCGA Pan-Cancer", "medianOS_mutated": null, "medianOS_wildtype": null, "n": 10967, "nMutated": null, "nWildtype": null, "pValue": null, "source": "TCGA", "studyId": "tcga_pan_can_atlas_2018", "survivalLabel": "no_data" } ], "cohortCount": 0, "consensusLabel": "no_data", "gene": "LRRK2", "heterogeneous": false, "meta": null, "totalPatients": 0 }, "PARK7": { "analyzedAt": "2026-05-01T15:02:39.805Z", "cohortBreakdown": [ { "error": "no_clinical_data", "hr": null, "label": "TCGA Pan-Cancer", "medianOS_mutated": null, "medianOS_wildtype": null, "n": 10967, "nMutated": null, "nWildtype": null, "pValue": null, "source": "TCGA", "studyId": "tcga_pan_can_atlas_2018", "survivalLabel": "no_data" } ], "cohortCount": 0, "consensusLabel": "no_data", "gene": "PARK7", "heterogeneous": false, "meta": null, "totalPatients": 0 }, "SNCA": { "analyzedAt": "2026-05-01T15:02:39.805Z", "cohortBreakdown": [ { "error": "no_clinical_data", "hr": null, "label": "TCGA Pan-Cancer", "medianOS_mutated": null, "medianOS_wildtype": null, "n": 10967, "nMutated": null, "nWildtype": null, "pValue": null, "source": "TCGA", "studyId": "tcga_pan_can_atlas_2018", "survivalLabel": "no_data" } ], "cohortCount": 0, "consensusLabel": "no_data", "gene": "SNCA", "heterogeneous": false, "meta": null, "totalPatients": 0 } } }, "multiOmicsPortrait": { "available": true, "conflictSummary": { "averageConflictIndex": 0, "convergentGenes": 0, "flaggedGenes": 0, "highestConflictGene": null, "highestConflictIndex": 0 }, "diseaseContext": "Parkinson's disease", "diseaseTissueFocus": [ "Brain (frontal cortex)", "Brain (hippocampus)", "Brain (substantia nigra)" ], "genes": [ { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 34.2, "cellxgene": { "atlas": "CELLxGENE brain single-cell atlas", "cellType": "dopaminergic neurons (substantia nigra)", "compartment": "neural", "detectionFraction": 0.57, "direction": "up", "diseaseMatched": true, "enrichment": 0.81, "stateLabel": "kinase-overactive dopaminergic state" }, "classification": "emerging omics signal", "cptac": { "cohort": "CPTAC Parkinson Brain Proteome", "direction": "up", "diseaseMatched": true, "evidenceTier": "cohort_matched", "phosphoSignal": 1.8, "phosphoState": "ser1292 autophosphorylation elevated", "proteinAbundanceZ": 1.3, "significant": true }, "crossOmicsConflict": { "directionalSignals": 2, "index": 0, "notes": [], "offContextModalities": [], "penaltyPoints": 0, "state": "sparse", "supportingModalities": 2 }, "depMap": { "essentialFraction": 0.004, "isStrongTarget": false, "meanChronos": -0.147, "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.438, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": -0.238, "tissue": "testis" } ] }, "evidenceBadges": [ "Structured target", "CPTAC protein gain", "Single-cell neural" ], "foldChange": null, "gene": "PARK7", "gtex": null, "hmdb": null, "modalityOutlook": "follow-up profiling required", "narrative": "CPTAC shows protein gain in CPTAC Parkinson Brain Proteome (protein z 1.3, phospho 1.8). CELLxGENE places the signal in dopaminergic neurons (substantia nigra) (neural compartment). DepMap classifies it as non-essential / poor target (Chronos -0.147). AlphaFold indicates well-structured (high classical druggability). Implication: follow-up profiling required.", "omicsPriorityScore": 34.2, "scoreAdjustments": { "conflictPenaltyPoints": 0, "survivalBoostPoints": 0 }, "scores": { "dependency": 4.02, "foldChange": 0, "metabolic": 0, "proteomics": 9.76, "singleCell": 8.58, "structure": 11.88, "tissue": 0 }, "structure": { "druggabilityLabel": "well-structured (high classical druggability)", "druggabilityScore": 99, "meanPlddt": 98.4, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-Q99497-F1-model_v6.pdb" }, "survivalCalibration": { "available": false, "boostPoints": 0, "matchMode": "none", "matched": false, "note": null, "patientCount": 0, "supportLevel": "none" } }, { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 13.1, "cellxgene": null, "classification": "emerging omics signal", "cptac": null, "crossOmicsConflict": { "directionalSignals": 0, "index": 0, "notes": [], "offContextModalities": [], "penaltyPoints": 0, "state": "sparse", "supportingModalities": 0 }, "depMap": { "essentialFraction": 0, "isStrongTarget": false, "meanChronos": 0.142, "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 1, "essentialFraction": 0, "meanScore": -0.016, "tissue": "adrenal gland" }, { "cellLineCount": 5, "essentialFraction": 0, "meanScore": 0.059, "tissue": "testis" } ] }, "evidenceBadges": [], "foldChange": null, "gene": "LRRK2", "gtex": null, "hmdb": null, "modalityOutlook": "follow-up profiling required", "narrative": "DepMap classifies it as non-essential / poor target (Chronos 0.142). AlphaFold indicates mostly structured (moderate druggability). Implication: follow-up profiling required.", "omicsPriorityScore": 13.1, "scoreAdjustments": { "conflictPenaltyPoints": 0, "survivalBoostPoints": 0 }, "scores": { "dependency": 4, "foldChange": 0, "metabolic": 0, "proteomics": 0, "singleCell": 0, "structure": 9.12, "tissue": 0 }, "structure": { "druggabilityLabel": "mostly structured (moderate druggability)", "druggabilityScore": 76, "meanPlddt": 77.5, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-Q5S007-F1-model_v6.pdb" }, "survivalCalibration": { "available": false, "boostPoints": 0, "matchMode": "none", "matched": false, "note": null, "patientCount": 0, "supportLevel": "none" } }, { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 12.8, "cellxgene": null, "classification": "emerging omics signal", "cptac": null, "crossOmicsConflict": { "directionalSignals": 0, "index": 0, "notes": [], "offContextModalities": [], "penaltyPoints": 0, "state": "sparse", "supportingModalities": 0 }, "depMap": { "essentialFraction": 0.004, "isStrongTarget": false, "meanChronos": -0.149, "tier": "non_essential", "tierLabel": "Non-essential / poor target", "tissueEssentiality": [ { "cellLineCount": 5, "essentialFraction": 0, "meanScore": -0.267, "tissue": "testis" }, { "cellLineCount": 11, "essentialFraction": 0, "meanScore": -0.202, "tissue": "thyroid gland" } ] }, "evidenceBadges": [], "foldChange": null, "gene": "SNCA", "gtex": null, "hmdb": null, "modalityOutlook": "follow-up profiling required", "narrative": "DepMap classifies it as non-essential / poor target (Chronos -0.149). AlphaFold indicates mostly structured (moderate druggability). Implication: follow-up profiling required.", "omicsPriorityScore": 12.8, "scoreAdjustments": { "conflictPenaltyPoints": 0, "survivalBoostPoints": 0 }, "scores": { "dependency": 4.02, "foldChange": 0, "metabolic": 0, "proteomics": 0, "singleCell": 0, "structure": 8.76, "tissue": 0 }, "structure": { "druggabilityLabel": "mostly structured (moderate druggability)", "druggabilityScore": 73, "meanPlddt": 75.2, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-P37840-F1-model_v6.pdb" }, "survivalCalibration": { "available": false, "boostPoints": 0, "matchMode": "none", "matched": false, "note": null, "patientCount": 0, "supportLevel": "none" } } ], "panelSummary": { "biomarkerCandidates": [], "cautions": [ "No uploaded differential-expression evidence was provided for this run.", "PARK7 show protein-level dysregulation without dependency support, so interventionability remains uncertain." ], "dominantSignals": [ "1 gene are reinforced by CPTAC protein-level signal.", "1 gene localize to high-enrichment CELLxGENE single-cell states.", "1 gene have high-confidence AlphaFold structure support." ], "narrative": "Top multi-omics priorities for Parkinson's disease are PARK7, LRRK2, SNCA. 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Single-cell data localizes the signal to dopaminergic neurons (substantia nigra).", "diseaseSignalReduction": 0.48, "druggability": 0.85, "feasibility": 0.812, "offTargetEffects": 0.1, "pathwayReversal": 0.022, "specificityIndex": 0.9 }, "rationale": [ "DepMap: Non-essential / poor target (Chronos -0.147)", "CPTAC: CPTAC Parkinson Brain Proteome protein gain (z 1.3)", "CELLxGENE: dopaminergic neurons (substantia nigra) neural signal", "AlphaFold: pLDDT 98.4" ] }, { "confidence": 0.7649999999999999, "description": "What if F52 was completely inhibited?", "doOperator": "do(PARK7=off)", "downstreamNodes": [], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.738, "confidence": 0.765, "counterfactualScore": 0.352, "description": "do(PARK7=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 2% pathway reversal support. 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