01At a glance
02What it is
Hereditary transthyretin amyloidosis is an autosomal dominant disease in which mutant transthyretin misfolds and forms amyloid deposits in nerves and heart, causing progressive neuropathy and cardiomyopathy. It is a toxic gain-of-function amyloidosis; approved therapies silence or stabilise the amyloidogenic protein, and selective degraders are the next frontier.
03What goes wrong
Gain-of-function / toxic aggregate. Mutant transthyretin (TTR) is destabilized and misfolds, dissociating from its native homotetramer and aggregating into amyloid fibrils that deposit in peripheral nerves and heart. This causes progressive sensorimotor/autonomic neuropathy and infiltrative cardiomyopathy. The amyloidogenic TTR is the toxic species.
04How NIGHTINGALE routes it
Recommended modality: silencer (siRNA/ASO approved) + stabilizer + selective degrader
ELIGIBLE. Amyloidogenic TTR is a toxic gain-of-function aggregate — reducing or degrading the misfolded TTR is mechanistically appropriate. Approved therapies (patisiran, inotersen) already work by *silencing* TTR production; a selective degrader of amyloidogenic TTR is the same logic via a different route.
05Treatment today
Patisiran (Onpattro)
2018-08-10 (Alnylam, NDA 211172)A small interfering RNA (siRNA) that degrades TTR mRNA, reducing hepatic transthyretin production and thereby lowering amyloidogenic TTR levels. It is NOT a small molecule and does not degrade the protein directly.
06In the pipeline
- Inotersen (Tegsedi) — antisense oligonucleotide TTR silencer (approved 2018)
- TTR stabilizers: tafamidis (Vyndaqel) — binds native tetramer, prevents dissociation (approved 2019)
- Selective TTR degraders (PROTAC/AUTOTAC) — preclinical
- CRISPR/Cas9 in vivo TTR gene editing (clinical, e.g. NTLA-2001)
Key reference: PMID 33188616 · PubMed
07Verification
Every line below is the registry's own verification record — what was checked, against which source, and what is still open.
- uniprot: P02766 = TTR (Transthyretin), 147 aa — VERIFIED via UniProt REST API (live)
- gene mutation: TTR missense mutations (Val30Met most common) — VERIFIED (OMIM 105210; FDA NDA 211172 review)
- inheritance: Autosomal dominant — VERIFIED (OMIM 105210; Orphanet; FDA NDA review)
- orpha code: 271861 = Hereditary ATTR amyloidosis (Active) — VERIFIED via Orphanet API (live, 2026-07-02)
- drug mw: Patisiran is an siRNA (not a small molecule) — MW/CID NOT APPLICABLE (left 0, not fabricated)
- fda date: 2018-08-10 (NDA 211172) — VERIFIED via FDA (live)
08Sources
| Fact | Source | Accession | Retrieved |
|---|---|---|---|
| Gene/protein identity | UniProt | P02766 (TTR, Transthyretin, 147 aa) | 2026-10-04 |
| Disease classification & definition | Orphanet | ORPHAcode 271861 (Hereditary ATTR amyloidosis) | 2026-10-04 |
| Inheritance & genetics | OMIM | 105210 (Transthyretin Amyloidosis) | 2026-10-04 |
| FDA approval (RNAi therapy) | FDA | NDA 211172 (Onpattro/patisiran, 2018-08-10) | 2026-10-04 |
Corrections carried into registry v2 (3)
- VERIFIED (2026-10-04): built fresh. ORPHAcode 271861 confirmed live via Orphanet API.
- CLARIFIED: patisiran silences TTR mRNA (does NOT bind or degrade the protein directly) — the mechanism is RNA-level reduction of the toxic protein.
- CLARIFIED: TTR amyloidosis is a toxic gain-of-function — AUTOTAC/degrader eligible (silencing/stabilizing/degradaing the amyloidogenic TTR are all valid directions).