ID: h-6b489d1dee
Hypothesis

Autophagy Enhancement via mTOR Inhibition for C9orf72 Dipeptide Repeat Pathology

C9orf72 repeat expansions produce toxic dipeptide repeats (DPRs) that impair nucleocytoplasmic transport and autophagy.
🧬 MTOR/C9orf72🩺 neurodegeneration🎯 Composite 49%💱 $0.51▲0.4%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates 3 support 3 oppose
✓ All Quality Gates Passed
Mechanistic 0.52 (15%) Evidence 0.55 (15%) Novelty 0.58 (12%) Feasibility 0.40 (12%) Impact 0.52 (12%) Druggability 0.55 (10%) Safety 0.42 (8%) Competition 0.50 (6%) Data Avail. 0.48 (5%) Reproducible 0.45 (5%) KG Connect 0.50 (8%) 0.490 composite

🧪 Overview

C9orf72 repeat expansions produce toxic dipeptide repeats (DPRs) that impair nucleocytoplasmic transport and autophagy. mTOR inhibition via rapamycin may reduce DPR accumulation. However, rapamycin benefits in Drosophila C9 models did not translate well to mammals, and C9 ASO programs have failed clinically.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix3 supports3 contradicts
Supports
Poly-GA DPRs aggregate with RBP4 and impair proteasome/autophagy
Supports
C9orf72 knockout in mice causes lysosomal accumulation and neurodegeneration
Supports
Rapamycin ameliorates neurodegeneration in Drosophila C9 models
Contradicts
Rapamycin has limited efficacy in mouse C9 models compared to Drosophila
Contradicts
BIIB078 C9 ASO discontinued after Phase 1 did not show clinical benefit
Contradicts
mTOR inhibition may impair other critical neuronal pathways
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — MTOR

No curated PDB or AlphaFold mapping for MTOR yet. Search RCSB →

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for MTOR →

No DepMap CRISPR Chronos data found for MTOR.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

🏆 Tournament

🏆 Arenas / Elo

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📊 Market Indicators

7d Trend
Stable
7d Momentum
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Volatility
Low
0.0001
Events (7d)
0
Price History
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💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
sourcev1_phase_c_backfill
origin_typedebate_synthesizer
_schema_version1
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting 0 contradicting 0 neutral
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