ID: h-fb25a50427
Hypothesis

C9orf72 repeat RNA and dipeptide-repeat toxicity in ALS/FTD

C9orf72 hexanucleotide repeat expansion produces repeat RNA foci and RAN-translated dipeptide-repeat proteins that disrupt nucleocytoplasmic transport, translation, stress granules, and neuronal survival.
🧬 C9orf72🩺 neurodegeneration🎯 Composite 70%💱 $0.60▼13.7%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates 4 support 2 oppose
✓ All Quality Gates Passed
Mechanistic 0.84 (15%) Evidence 0.82 (15%) Novelty 0.62 (12%) Feasibility 0.66 (12%) Impact 0.78 (12%) Druggability 0.74 (10%) Safety 0.56 (8%) Competition 0.50 (6%) Data Avail. 0.80 (5%) Reproducible 0.72 (5%) KG Connect 0.50 (8%) 0.700 composite

🧪 Overview

C9orf72 hexanucleotide repeat expansion produces repeat RNA foci and RAN-translated dipeptide-repeat proteins that disrupt nucleocytoplasmic transport, translation, stress granules, and neuronal survival. The strongest program should not be DPR-only; it should separately interrogate sense RNA, antisense RNA, DPRs, and C9orf72 haploinsufficiency.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix4 supports2 contradicts
Supports
C9orf72 repeat expansion is the most common genetic cause of ALS/FTD.
Supports
Dipeptide-repeat proteins accumulate in patient neurons and are linked to pathology.
Supports
Poly-GR and poly-PR disrupt nuclear import in model systems.
Supports
Antisense oligonucleotide reduction of repeat products improves phenotypes in preclinical models.
Contradicts
DPR reduction alone may be insufficient, as BIIB078 reduced target biomarkers without clinical benefit.
Contradicts
Persistent CNS pathologies after target engagement weaken a simple DPR-only therapeutic model.
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — C9ORF72

No curated PDB or AlphaFold mapping for C9ORF72 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 C9orf72 →

No DepMap CRISPR Chronos data found for C9orf72.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

🏆 Tournament

🏆 Arenas / Elo

No arena matches recorded yet. Browse Arenas →

📊 Market Indicators

7d Trend
Falling
7d Momentum
▼ 1.9%
Volatility
Low
0.0023
Events (7d)
4
Price History
▼13.7%

💾 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
Public annotations (0)Annotate on Hypothes.is →
No public annotations yet.