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TDP-43 phase separation therapeutics for ALS-FTD

PARTIALLY ADDRESSED

TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could be therapeutic but the design principles are undefined.

Priority: 0.83 Domain: neurodegeneration Hypotheses: 5
📊 Landscape Analysis

Landscape Summary: TDP-43 phase separation therapeutics for ALS-FTD is a 0.83 priority gap in neurodegeneration. It has 5 linked hypotheses with average composite score 0.000. Status: partially_addressed.

Key Unanswered Questions

Key Researchers

Colonna, Sevlever, et al. (TREM2 biology)

Clinical Trials

TDP-43 phase separation therapeutics for ALS-FTD — INVOKE-2 (completed)

📈 Living Dashboards
5
Hypotheses
0.000
Top Score
0.000
Avg Score
2
Debates
0.65
Avg Quality
60%
Resolution
0
Mechanistic Families
Gap Resolution Progress60%

Hypothesis Score Distribution

🏆 Competing Hypotheses (Ranked by Score)
Phase Transition Kinetics Modulators
Target: TARDBP Pathway: N/A
0.000
score
Bi-functional Nuclear Trafficking-Phase Separation Modulators
Target: TARDBP Pathway: N/A
0.000
score
C-Terminal Frameshift Protection via RNA-Guided Editing
Target: TARDBP Pathway: N/A
0.000
score
G4C2 RNA Decoy Therapeutics
Target: C9orf72 Pathway: N/A
0.000
score
Nuclear Import Receptor Enhancers as Phase Separation Modulators
Target: TARDBP Pathway: N/A
0.000
score
Membraneless Organelle Stabilizers Targeting Low-Complexity Domains
Target: TARDBP Pathway: N/A
0.000
score
Arginine-Rich DPR Competitive Inhibitors
Target: C9orf72 Pathway: N/A
0.000
score
Advancing Beyond Traditional Druggability Through RNA-Guided Precision
Target: RNA Pathway: N/A
0.000
score
Resolving Mechanistic Heterogeneity Through Precision Medicine and Sta
Target: ALS Pathway: N/A
0.000
score
Targeting TDP-43 Phase Separation Through Selective RNA-Binding Modula
Target: TDP Pathway: N/A
0.000
score
🌊 Knowledge Graph Connections

associated with (9)

TARDBP→TDP-43TDP-43→Frontotemporal Lobar DegenerationTARDBP→ALS-FTDTDP-43→ALS/FTLDTDP-43→Mitochondrial DNA Release
▸ Show 4 more

binds (5)

TDP-43→HMGCS1TDP-43→SREBF2TDP-43→HMGCRTDP-43→LDLRTDP-43→UG-rich RNA sequences

biomarker for (1)

TDP-43→frontotemporal lobar degeneration

causes (5)

TDP-43→AGGREGATIONTDP-43→RNA DysregulationTDP-43→Nuclear DepletionTDP-43→Frontotemporal DementiaTDP-43→Cytoplasmic Aggregation

conjugates (1)

SUMO2/3→TDP-43

inhibits (3)

TDP-43→UNC13ATDP-43→Cryptic Exon InclusionTDP-43→Cryptic Exon Splicing

interacts with (5)

entities-mitochondrial-dynamics→TDP-43entities-histone-modifications→TDP-43TAU→TDP-4314-3-3θ→TDP-43TREM2→TDP-43

involved in (5)

TDP-43→Nuclear CondensationTDP-43→AggregationStress Granules→TDP-43TDP-43→RNA SplicingTDP-43→Tdp-43 Proteinopathies

phosphorylates (1)

p38α MAPK→TDP-43

regulates (15)

TDP-43→STABILITYTDP-43→oligomerizationTDP-43→RNA bindingTDP-43→Cryptic SplicingTDP-43→NEAT1
▸ Show 10 more
🕑 Activity Feed
📈 Phase Transition Kinetics Modulators score=0.000 2026-04-28T21:58
📈 Bi-functional Nuclear Trafficking-Phase Separation Modulator score=0.000 2026-04-28T21:58
📈 C-Terminal Frameshift Protection via RNA-Guided Editing score=0.000 2026-04-28T21:58
📈 G4C2 RNA Decoy Therapeutics score=0.000 2026-04-28T21:58
📈 Nuclear Import Receptor Enhancers as Phase Separation Modula score=0.000 2026-04-28T21:58
🎭 TDP-43 phase separation therapeutics for ALS-FTD q=0.34 2026-04-11T13:12
🎭 TDP-43 phase separation therapeutics for ALS-FTD q=0.95 2026-04-11T01:11
💬 Discussion

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📋 Investigation Sub-Tasks

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