01At a glance
02What it is
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. It causes progressive motor dysfunction (chorea), cognitive decline, and psychiatric symptoms, typically beginning in mid-adulthood. Mutant huntingtin forms toxic aggregates in striatal neurons. Current treatment is symptomatic only; allele-selective degradation and ASO silencing are the leading disease-modifying frontiers.
03What goes wrong
Gain-of-function / toxic aggregate. The expanded CAG repeat encodes an abnormally long polyglutamine (polyQ) tract in the huntingtin N-terminus. Mutant huntingtin aggregates, disrupts proteostasis, and is toxic to striatal medium spiny neurons. Note: mutant huntingtin is also thought to lose some normal function (loss-of-function component), but the dominant disease driver is the toxic gain-of-function.
04How NIGHTINGALE routes it
Recommended modality: allele-selective degrader + ASO silencing (investigational)
ELIGIBLE. Mutant huntingtin is a toxic gain-of-function aggregate — a canonical target for selective degradation. Degrading mutant huntingtin (ideally allele-selectively, sparing wild-type huntingtin) is mechanistically appropriate. No degrader is yet approved; this is an active research frontier.
05Treatment today
Deutetrabenazine (Austedo)
2017-04-03 (Teva)Inhibits vesicular monoamine transporter 2, reducing chorea (involuntary movements). It is SYMPTOMATIC ONLY — it does not modify disease progression or reduce mutant huntingtin.
06In the pipeline
- Antisense oligonucleotides (ASO) targeting HTT mRNA (tominersen/RG6042 — Phase 3 halted; others ongoing)
- Allele-selective mutant huntingtin degraders (PROTAC/AUTOTAC, preclinical)
- CRISPR/Cas9 HTT gene silencing (preclinical)
- Small-molecule splicing modulators of HTT
Key reference: PMID 34413240 · PubMed
07Verification
Every line below is the registry's own verification record — what was checked, against which source, and what is still open.
- uniprot: P42858 = HTT (Huntingtin), 3142 aa — VERIFIED via UniProt REST API (live)
- gene mutation: CAG repeat expansion in HTT exon 1 (polyglutamine expansion) — VERIFIED (Nature Cell Biology 2024; Nature Rev Neurol 2020)
- inheritance: Autosomal dominant — VERIFIED (OMIM 143100; Orphanet)
- orpha code: 399 = Huntington disease (Active) — VERIFIED via Orphanet API (live, 2026-07-02)
- drug mw: 323.5 Da, CID 73442840, C19H27NO3 — VERIFIED via PubChem REST API (live)
- fda date: Deutetrabenazine 2017-04-03 — commonly cited; exact NDA not re-verified this session
08Sources
| Fact | Source | Accession | Retrieved |
|---|---|---|---|
| Gene/protein identity | UniProt | P42858 (HTT, Huntingtin, 3142 aa) | 2026-10-04 |
| Disease classification & definition | Orphanet | ORPHAcode 399 (Huntington disease) | 2026-10-04 |
| Inheritance & genetics | OMIM | 143100 (Huntington Disease) | 2026-10-04 |
| Drug molecular weight | PubChem | CID 73442840 (deutetrabenazine, 323.5 Da, C19H27NO3) | 2026-10-04 |
| PolyQ aggregation mechanism | Nature Cell Biology 2024 | Polyglutamine-mediated ribotoxicity (Aviner et al. 2024) | 2026-10-04 |
Corrections carried into registry v2 (3)
- VERIFIED (2026-10-04): built fresh. ORPHAcode 399 confirmed live via Orphanet API.
- CLARIFIED: deutetrabenazine is SYMPTOMATIC (chorea) only, not disease-modifying — this distinction is essential and was often omitted in prior data.
- CLARIFIED: HD has BOTH a toxic gain-of-function (aggregation) AND a loss-of-function component; the primary driver is gain-of-function, which is why AUTOTAC is eligible.