{ "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-010", "disease_name": "Alpha-1 Antitrypsin Deficiency", "short_name": "A1AT Deficiency / AATD", "gene": "SERPINA1", "uniprot": "P01009", "protein_name": "Alpha-1-antitrypsin (Serpin A1)", "protein_length_aa": 418, "omim_id": 613490, "orpha_code": 60, "category": "Metabolic / Serpinopathy", "inheritance": "Autosomal co-dominant — SERPINA1 Z allele (Glu342Lys, the PI*Z variant) homozygosity is the most common severe form", "mechanism": "Dual mechanism. (1) Gain-of-function in the liver: the Z-variant alpha-1-antitrypsin misfolds and polymerizes, accumulating in hepatocyte endoplasmic reticulum, causing liver injury, fibrosis, and cirrhosis. (2) Loss-of-function in the lung: reduced circulating A1AT (a serine protease inhibitor) leaves the lung unprotected from neutrophil elastase, causing early-onset emphysema. The liver toxicity is the toxic-gain-of-function component.", "mechanism_class": "dual_gof_lof", "recommended_modality": "augmentation (LoF) + polymer blocker/degrader (GoF, investigational)", "autotac_eligible": false, "autotac_rationale": "COMPLEX — NOT a blanket 'eligible'. The liver disease is a toxic gain-of-function (Z-AAT polymerization), so a selective degrader of polymerized Z-AAT is mechanistically plausible for the HEPATIC component. However the lung disease is loss-of-function (deficient antiprotease), where degradation would worsen it. AUTOTAC is NOT appropriate for the disease as a whole — only a targeted hepatic strategy would qualify. The approved therapy is augmentation (restore the missing antiprotease), which addresses the LoF component.", "prevalence": "~1 in 2,500-5,000 (PI*ZZ, European descent) — commonly cited; UNVERIFIED exact figure this session", "age_of_onset": "Lung: early adulthood (emphysema, worse with smoking); Liver: infancy (cholestatic jaundice) to adulthood (cirrhosis)", "approved_treatments": [ { "drug": "Alpha-1 Proteinase Inhibitor (human, e.g. Prolastin-C / Zemaira / Aralast)", "mw_da": null, "pubchem_cid": null, "class": "Augmentation therapy (purified human A1AT)", "mechanism_correct": "Intravenous infusion of purified human alpha-1-antitrypsin to restore circulating antiprotease levels, protecting the lung from elastase-mediated damage. Addresses the loss-of-function component only; does not clear hepatic Z-AAT polymers.", "fda_approval": "1987 (first A1AT augmentation products)", "fda_nda": "", "note": "NOTE: A1AT augmentation is a pooled human plasma-derived protein (~52 kDa), NOT a small molecule — MW/PubChem CID left 0 to avoid fabrication.", "mw_note": "biologic — molecular weight not applicable" } ], "combination_therapy": "", "investigational": [ "Small-molecule polymerisation blockers (e.g. targeting the Z-AAT polymer interface — JCI Insight 2025)", "Selective degraders of polymerized Z-AAT (autophagy enhancers / PROTAC) — preclinical, for the hepatic component", "siRNA silencing of SERPINA1 (e.g. fazirsiran/ARO-AAT — clinical)", "Gene therapy / CRISPR correction (preclinical)" ], "clinical_trials_count": 25, "key_pmid": 32268028, "references": [ { "fact": "Gene/protein identity", "source": "UniProt", "accession": "P01009 (SERPINA1, Alpha-1-antitrypsin, 418 aa)", "url": "https://rest.uniprot.org/uniprotkb/P01009", "retrieved": "2026-10-04" }, { "fact": "Disease classification & definition", "source": "Orphanet", "accession": "ORPHAcode 60 (Alpha-1-antitrypsin deficiency)", "url": "https://www.orpha.net/en/disease/detail/60", "retrieved": "2026-10-04" }, { "fact": "Inheritance & genetics", "source": "OMIM", "accession": "613490 (Alpha-1-antitrypsin deficiency)", "url": "https://omim.org/entry/613490", "retrieved": "2026-10-04" }, { "fact": "Z-AAT polymerisation (gain-of-function) mechanism", "source": "JCI Insight 2025", "accession": "Ronzoni et al., polymer-blocking therapy (10.1172/jci.insight.194354)", "url": "https://doi.org/10.1172/jci.insight.194354", "retrieved": "2026-10-04" }, { "fact": "Disease review", "source": "N Engl J Med 2020", "accession": "32268028", "url": "https://pubmed.ncbi.nlm.nih.gov/32268028/", "retrieved": "2026-11-02" } ], "verification": { "uniprot": "P01009 = SERPINA1 (Alpha-1-antitrypsin), 418 aa — VERIFIED via UniProt REST API (live)", "gene_mutation": "SERPINA1 Z allele (Glu342Lys / PI*Z) — VERIFIED (OMIM 613490; literature)", "inheritance": "Autosomal co-dominant — VERIFIED (OMIM 613490; Orphanet)", "orpha_code": "60 = Alpha-1-antitrypsin deficiency (Active) — VERIFIED via Orphanet API (live, 2026-07-02)", "drug_mw": "A1AT augmentation is a plasma-derived protein (~52 kDa), not a small molecule — MW/CID NOT APPLICABLE (left 0, not fabricated)", "fda_date": "A1AT augmentation products 1987 — commonly cited; exact NDA not re-verified this session" }, "corrections_from_prior": [ "VERIFIED (2026-10-04): built fresh. ORPHAcode 60 confirmed live via Orphanet API.", "CLARIFIED: A1AT deficiency is a DUAL-mechanism disease — liver (toxic GoF polymerisation) + lung (LoF antiprotease deficiency). AUTOTAC is NOT a blanket 'eligible' — only the hepatic component is a plausible degrader target.", "CLARIFIED: augmentation therapy addresses the LoF (lung) component only; it does not clear hepatic Z-AAT polymers." ], "human_summary": "Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder caused by the SERPINA1 Z allele, whose protein product polymerizes and accumulates in the liver (causing cirrhosis) while deficient circulating antiprotease leaves the lungs vulnerable to emphysema. It is a dual gain-of-function (liver) and loss-of-function (lung) disease; augmentation therapy treats the lung component.", "clinical_trials_total": 147, "clinical_trials_note": "25 curated interventional trials; 147 ClinicalTrials.gov studies in total (2026-11-02)" } }