{ "registry_version": "v2.0-fresh-2026-10-04", "protocol": "TJ Compassion + L.O.V.E. — every fact live-verified against UniProt / PubChem / ClinVar / OMIM / FDA / Orphanet", "disease": { "id": "ORPHAN-002", "disease_name": "Friedreich Ataxia", "short_name": "FRDA", "gene": "FXN", "uniprot": "Q16595", "protein_name": "Frataxin, mitochondrial (mature form Frataxin 81-210)", "protein_length_aa": 210, "omim_id": 229300, "orpha_code": 95, "category": "Neurodegenerative / Trinucleotide Repeat", "inheritance": "Autosomal recessive — biallelic GAA trinucleotide repeat expansion in intron 1 of FXN", "mechanism": "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 to ~5-30% of normal, impairing mitochondrial iron-sulfur cluster (ISC) biogenesis and leading to iron accumulation and oxidative stress.", "mechanism_class": "enzyme_lof", "recommended_modality": "upregulator (Nrf2 activator approved) + gene therapy (investigational)", "autotac_eligible": false, "autotac_rationale": "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.", "prevalence": "1–9 per 100,000 (Orphanet); ~1 in 20,000–1 in 50,000 in people of Caucasian descent", "age_of_onset": "Typically 5-15 years (gait ataxia); can be later in milder forms", "approved_treatments": [ { "drug": "Omaveloxolone (Skyclarys)", "mw_da": 554.7, "pubchem_cid": 71811910, "class": "Nrf2 activator", "mechanism_correct": "Activates the Nrf2 antioxidant pathway, reducing oxidative stress and improving mitochondrial function. It does NOT restore frataxin expression directly; it mitigates downstream oxidative damage.", "fda_approval": "2023-02-28 (Reata Pharmaceuticals, NDA 216718)", "fda_nda": "216718", "note": "First FDA-approved therapy for FRDA (2023). Slows decline; not curative." } ], "combination_therapy": "", "investigational": [ "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" ], "clinical_trials_count": 12, "key_pmid": "18725397", "references": [ { "fact": "Gene/protein identity", "source": "UniProt", "accession": "Q16595 (FXN, Frataxin mitochondrial, 210 aa)", "url": "https://rest.uniprot.org/uniprotkb/Q16595", "retrieved": "2026-10-04" }, { "fact": "Disease classification & definition", "source": "Orphanet", "accession": "ORPHAcode 95 (Friedreich ataxia)", "url": "https://www.orpha.net/en/disease/detail/95", "retrieved": "2026-11-02" }, { "fact": "Inheritance & genetics", "source": "OMIM", "accession": "229300 (Friedreich Ataxia, FRDA)", "url": "https://omim.org/entry/229300", "retrieved": "2026-10-04" }, { "fact": "GAA repeat silencing mechanism", "source": "PMC", "accession": "PMC4654050 (expanded GAA repeats impede transcription elongation and induce FXN silencing)", "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC4654050/", "retrieved": "2026-10-04" }, { "fact": "Drug molecular weight", "source": "PubChem", "accession": "CID 71811910 (omaveloxolone, 554.7 Da)", "url": "https://pubchem.ncbi.nlm.nih.gov/rest/pug/compound/cid/71811910/property/MolecularWeight/JSON", "retrieved": "2026-10-04" }, { "fact": "FDA approval", "source": "FDA", "accession": "NDA 216718 (Skyclarys/omaveloxolone, 2023-02-28)", "url": "https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216718Orig1s000Approv.pdf", "retrieved": "2026-10-04" }, { "fact": "MHRA approval / access", "source": "MHRA", "accession": "Omaveloxolone approved 2025-04-23", "url": "https://www.gov.uk/government/news/mhra-approves-first-uk-treatment-for-friedreichs-ataxia-omaveloxolone", "retrieved": "2026-11-02" }, { "fact": "NICE approval / access", "source": "NICE", "accession": "TA1061 terminated 2025-05-06", "url": "https://www.nice.org.uk/guidance/ta1061", "retrieved": "2026-11-02" }, { "fact": "SMC approval / access", "source": "SMC", "accession": "SMC2845 not recommended 2026-03-09", "url": "https://scottishmedicines.org.uk/medicines-advice/omaveloxolone-skyclarys-full-smc2845", "retrieved": "2026-11-02" }, { "fact": "ClinicalTrials.gov approval / access", "source": "ClinicalTrials.gov", "accession": "115 studies in total (2026-11-02)", "url": "https://clinicaltrials.gov/search?cond=Friedreich%20Ataxia", "retrieved": "2026-11-02" }, { "fact": "RCSB PDB approval / access", "source": "RCSB PDB", "accession": "3T3K — Q148R frataxin construct, 1.24 Å", "url": "https://www.rcsb.org/structure/3T3K", "retrieved": "2026-11-02" }, { "fact": "Frataxin level", "source": "GeneReviews", "accession": "NBK1281 (Friedreich Ataxia)", "url": "https://www.ncbi.nlm.nih.gov/books/NBK1281/", "retrieved": "2026-11-02" } ], "verification": { "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)", "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)", "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)", "clinical_trials_total": "115 ClinicalTrials.gov studies in total; 12 curated interventional trials (2026-11-02)" }, "corrections_from_prior": [ "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." ], "human_summary": "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.", "clinical_trials_total": 115, "clinical_trials_note": "12 registry-listed trials; 115 ClinicalTrials.gov studies in total (2026-11-02)", "uk_access": "MHRA approved omaveloxolone on 2025-04-23. NICE TA1061 was terminated on 2025-05-06 after Biogen withdrew. SMC2845 did not recommend it on 2026-03-09. Not routinely available on the NHS; individual funding routes are discretionary.", "structural_note": "PDB 3T3K is the Q148R disease-variant construct covering residues 82–210; it is not wild-type frataxin or the full 210-residue precursor." } }