01At a glance
02What it is
Friedreich ataxia is the most common hereditary ataxia. Progressive gait and limb ataxia, dysarthria, and cardiomyopathy typically begin in adolescence. Most cases are caused by a GAA repeat expansion that silences frataxin, a mitochondrial protein needed for iron-sulfur cluster assembly.
03What goes wrong
Loss-of-function. The expanded GAA repeat in FXN intron 1 forms a triplex/heterochromatin structure that impedes transcription elongation and induces locus-specific transcriptional silencing of FXN. This reduces frataxin substantially — commonly cited as ~5–30% of normal — impairing mitochondrial iron-sulfur cluster (ISC) biogenesis and leading to iron accumulation and oxidative stress.
Structural note: the pipeline resolves FXN to PDB 3T3K, the Q148R disease-variant construct covering residues 82–210. It is not wild-type frataxin and not the full 210-residue precursor.
04How NIGHTINGALE routes it
Recommended modality: upregulator (Nrf2 activator approved) + gene therapy (investigational)
NOT eligible. FRDA is a loss-of-function disease — frataxin is depleted, not accumulated. Degrading frataxin further would worsen the disease. Correct route is frataxin restoration (upregulators, gene therapy), not protein degradation.
05Treatment today
Omaveloxolone (Skyclarys)
2023-02-28 (Reata Pharmaceuticals, NDA 216718)Activates the Nrf2 antioxidant pathway, reducing oxidative stress and improving mitochondrial function. It does NOT restore frataxin expression directly; it mitigates downstream oxidative damage.
UK access: The MHRA approved omaveloxolone on 23 April 2025. NICE TA1061 was terminated on 6 May 2025 after Biogen withdrew its submission, and SMC2845 did not recommend it on 9 March 2026. It is not routinely available on the NHS; individual funding routes exist but are discretionary.
06In the pipeline
- Frataxin gene therapy (AAV-mediated, preclinical/early clinical)
- Etravirine (NNRTI) — reported to increase frataxin expression (Phase 2 FAEST1, NCT04273165, COMPLETED Jan 2023)
- Omaveloxolone + idebenone (Nrf2 + mitochondrial antioxidant)
- Histone deacetylase inhibitors (e.g. HDAC3) — preclinical frataxin upregulation
Key reference (frataxin maturation): PMID 18725397 · PubMed
07Verification
Every line below is the registry's own verification record — what was checked, against which source, and what is still open.
- uniprot: Q16595 = FXN (Frataxin, mitochondrial), 210 aa precursor — VERIFIED via UniProt REST API (live)
- gene mutation: GAA repeat expansion in intron 1 of FXN — VERIFIED (PMC4654050: expanded GAA repeats impede transcription elongation + induce silencing)
- inheritance: Autosomal recessive — VERIFIED (OMIM 229300; Orphanet ORPHAcode 95)
- orpha code: 95 = Friedreich ataxia — VERIFIED via Orphanet public entry (accessed 2026-11-02)
- MHRA: omaveloxolone approved 2025-04-23 — VERIFIED (GOV.UK)
- NICE: TA1061 terminated 2025-05-06 — VERIFIED (NICE)
- SMC: SMC2845 not recommended 2026-03-09 — VERIFIED (SMC)
- drug mw: 554.7 Da, CID 71811910, C33H44F2N2O3 — VERIFIED via PubChem REST API (live)
- fda date: 2023-02-28 (NDA 216718) — VERIFIED via FDA accessdata (live)
08Sources
| Fact | Source | Accession | Retrieved |
|---|---|---|---|
| Gene/protein identity | UniProt | Q16595 (FXN, Frataxin mitochondrial, 210 aa) | 2026-10-04 |
| Disease classification & definition | Orphanet | ORPHAcode 95 (Friedreich ataxia) | 2026-10-04 |
| Inheritance & genetics | OMIM | 229300 (Friedreich Ataxia, FRDA) | 2026-10-04 |
| GAA repeat silencing mechanism | PMC | PMC4654050 (expanded GAA repeats impede transcription elongation and induce FXN silencing) | 2026-10-04 |
| Frataxin level | GeneReviews | Friedreich Ataxia (NBK1281) | 2026-11-02 |
| Drug molecular weight | PubChem | CID 71811910 (omaveloxolone, 554.7 Da) | 2026-10-04 |
| FDA approval | FDA | NDA 216718 (Skyclarys/omaveloxolone, 2023-02-28) | 2026-10-04 |
| UK approval | MHRA | Omaveloxolone approved 2025-04-23 | 2026-11-02 |
| NICE appraisal | NICE | TA1061 terminated 2025-05-06 | 2026-11-02 |
| Scottish appraisal | SMC | SMC2845 not recommended 2026-03-09 | 2026-11-02 |
| Clinical trial count | ClinicalTrials.gov | 115 studies in total; 12 registry-listed trials | 2026-11-02 |
| Structural target | RCSB PDB | 3T3K — Q148R frataxin construct, 1.24 Å | 2026-11-02 |
Corrections carried into registry v2 (6)
- FIXED: prior dossier cited PDB 1UXL as 'human frataxin' — it is actually SOD1 I113T mutant. Removed.
- FIXED: prior dossier had 6 of 8 PDB citations wrong (1UXL, 2CQN, 3BOW, 3IFZ, 3LZH, 4D2B). Correct frataxin structures are 1EKG (1.8 A), 3S4M, 3T3J.
- FIXED: etravirine dose listed as '200 mcg/day' — correct is 200 mg/day (1000x error). NCT04303156 -> NCT04273165 (FAEST1).
- FIXED: omaveloxolone approval date listed '2022-02-18' — correct is 2023-02-28.
- FIXED: prior data marked FRDA AUTOTAC 'uncertain/possibly eligible' — correct is NOT eligible (loss-of-function).
- VERIFIED (2026-10-04): ORPHAcode 95 confirmed live via Orphanet API.