HD-001
Huntington's Disease · CAG Repeat Expansion Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · NEURO ← RESEARCH
mHTT polyQ expansion
Striatal MSN dying
Nuclear inclusion body
CAG repeat units
γ₁ floor anchor
PHASES
RX
BIOMARKERS
EEG
NPs
Genetic Engine PROVEN
HTT Gene · CAG Repeat Expansion
Normal: 10–35 CAG. Reduced penetrance: 36–39. Full penetrance: ≥40. Juvenile onset: ≥60. Chr4p16.3. Autosomal dominant — one copy sufficient. 100% penetrance at ≥40 repeats.
MacDonald et al. 1993 Cell — HTT gene discovery. Huntington's Disease Collaborative Research Group.
CAG → Onset Age Formula
Mean onset ≈ 63.4 − 0.55×(CAG−35). CAG=42: ~53yr. CAG=50: ~38yr. CAG=60: ~15yr (juvenile). Population r²~0.7. SORRY: individual variance ±5–10yr due to somatic instability.
Andrew et al. 1993 · Langbehn et al. 2004 Clin Genet
mHTT Toxic Gain-of-Function
PolyQ expansion → misfolding → nuclear inclusions → transcription factor sequestration → MSN-specific death. Medium spiny neurons of caudate/putamen most vulnerable: high NMDA receptor density + low antioxidant reserve.
Scherzinger et al. 1997 Cell · Li & Li 2004 Trends Genet
Somatic CAG Instability
CAG expands further in somatic cells — especially brain. MLH1/MSH3 mismatch repair genes modulate somatic instability = significant onset modifier beyond germline CAG.
GeM-HD Consortium 2019 Cell · SORRY: not yet clinically actionable.
Chorea — Symptomatic
Tetrabenazine PROVEN
VMAT2 inhibitor. Depletes presynaptic DA. FDA-approved 2008. Side effects: depression, sedation, parkinsonism.
Huntington Study Group 2006 NEJM (TETRA-HD, n=84)
Deutetrabenazine PROVEN
Deuterated TBZ. Longer half-life, better tolerability. FDA-approved 2017 for HD chorea.
Frank et al. 2016 JAMA (ARC-HD)
Disease-Modifying — THE DEFINING SORRY
TOMINERSEN PHASE 3 FAILURE 2021 MAJOR SORRY
HTT-lowering ASO. ICV delivery. CSF mHTT reduced 40% — target engagement confirmed. GENERATION-HD1 (n=791) halted March 2021 by DSMB: futility + worse outcomes in high-dose arm. Mechanism of harm unknown.
Tabrizi et al. 2019 NEJM (Phase 1/2 — CSF reduction) · Kingwell 2021 Nat Rev Drug Discov (halt analysis)
Allele-Selective ASO (WVE-003) Phase 1/2
Targets SNP on mutant allele only. Preserves wild-type HTT — addresses tominersen's selectivity problem. Phase 1/2 ongoing.
SORRY: clinical data immature. Selectivity approach theoretically sound.
PTC518 Splicing Modifier Phase 2
Oral small molecule. Exon skipping → truncated mHTT. Brain penetrant. 50% HTT lowering at therapeutic dose.
Tabrizi et al. 2023 NEJM Evidence (Phase 2 interim)
Biomarkers
CAG count PROVENDiagnostic + prognostic. Only validated predictive biomarker in HD. SORRY: individual onset timing uncertain.
Caudate MRI PROVENAtrophy detectable 15yr pre-onset. TRACK-HD primary progression marker. Ross et al. 2014 Lancet Neurol
CSF mHTT PROVENQuantifiable pre-manifestly. Showed tominersen target engagement. SORRY: CSF sampling invasive.
Plasma NfL STRONGRises years before onset. Excellent non-invasive trial biomarker. Johnson et al. 2021 Nat Med
Somatic CAG EMERGINGBlood PCR somatic repeat expansion. Correlates better with onset than germline CAG. Not yet clinical standard.
EEG / Neurophysiology
γ-band disruptionReduced γ coherence (30–80Hz) frontal-striatal. Loss of fast-spiking interneurons in striatum → γ oscillation generator fails. Correlates with cognitive decline. SORRY: HD EEG less characterised than PD β or epilepsy waveforms.
Cortical slowingα-peak frequency reduction tracks cognitive deterioration. Non-specific.
Sleep spindle lossNREM spindles (12–15Hz) reduced early in HD. Predates manifest disease. Thalamo-cortical circuit disruption. Piano et al. 2017 Sleep
P300 prolongationERP P300 latency increased in pre-manifest HD. Cognitive processing slowing. Potential trial endpoint.
Motor cortex excit.TMS: cortical silent period shortened. Reduced cortical inhibition correlates with chorea. Lefaucheur 2005
Thinkbeat Bridge
Sleep spindle loss → γ-coherence disruption → global slowing maps to SLOW_MONOTONE → OSCILLATING → CHAOTIC. The CAG counter IS the δ-function: every repeat above 35 increases δ. Above 40: guaranteed CHAOTIC. The most mathematically honest disease in the fleet.
Novel Patterns (7)
PROVENNP-HD-001 · Only brain disease where onset is mathematically predictable from genetics · CAG → onset formula · MacDonald 1993 Cell
PROVENNP-HD-002 · 100% penetrance ≥40 CAG · autosomal dominant · no escape · one mutant copy is sufficient
PROVENNP-HD-003 · mHTT toxic gain-of-function · not loss of normal HTT · polyQ expansion creates new toxic property
PROVENNP-HD-004 · Caudate atrophy 15yr pre-symptom · longest pre-clinical structural window in neurodegeneration · TRACK-HD 2011 Lancet Neurol
OPENNP-HD-005 · Somatic CAG instability (MLH1/MSH3) = significant onset modifier · therapeutic target? · GeM-HD 2019 Cell
SORRYNP-HD-006 · Tominersen failure 2021 — HTT lowering worked but outcomes worsened · why? mechanism unknown
SORRYNP-HD-007 · No DMT approved 2026 · most genetically tractable brain disease · still no cure · the HD paradox
Open Sorries (5)
SORRY-1: Tominersen failure — CSF mHTT −40% confirmed, outcomes worsened. WT HTT depletion? Immune response? Unknown.
SORRY-2: Onset formula population-level only. Individual variance ±5–10yr due to somatic instability + MLH1/FAN1 modifiers.
SORRY-3: Why MSNs specifically? mHTT in every cell. NMDA/antioxidant hypothesis not definitively proven.
SORRY-4: Juvenile HD (CAG≥60) = different clinical syndrome (rigidity not chorea). Different mechanism? Poorly studied.
SORRY-5: Allele-selective ASOs (WVE-003) solve the WT problem theoretically. Clinical validation gap remains.
⚠ OPEN SORRIES · HD-001
SORRY-1 · Tominersen Failure (the big one)
ASO reduced CSF mHTT by 40% — target engagement confirmed. Phase 3 GENERATION-HD1 halted by DSMB March 2021. High-dose arm: worse outcomes than placebo. Mechanism unknown. Leading hypotheses: wild-type HTT depletion, immune-mediated CSF reaction, or mHTT clearance itself is harmful. The most important unanswered question in HD research.

SORRY-2 · Onset Formula vs Individual
Population r²~0.7. Somatic instability, MLH1/MSH3/FAN1 variants add ±5–10yr individual variance. Formula cannot tell an individual when they will become symptomatic.

SORRY-3 · Why MSNs?
mHTT expressed in every cell. Medium spiny neurons die first. Best explanation: high NMDA receptor density + mitochondrial vulnerability. Not definitively proven mechanistically.

SORRY-4 · Juvenile HD
CAG≥60 presents with rigidity-dominance not chorea. Qualitatively different pathomechanism at very high repeat lengths. Understudied population.

SORRY-5 · Allele-Selective Gap
WVE-003 solves the WT-depletion problem in theory. Phase 1/2 data immature. Clinical validation pending.
HD-001 · CAG REPEAT EXPANSION · 100% PENETRANT · 15YR PRE-CLINICAL WINDOW · TOMINERSEN FAILED · NO DMT
γ₁ = 14.134725141734693