01At a glance
02What it is
Cystic fibrosis is an autosomal recessive disorder caused by CFTR mutations, most commonly F508del, which misfolds the chloride channel and prevents it reaching the cell surface. It causes progressive lung disease, pancreatic insufficiency, and male infertility. CFTR modulator drugs (correctors + potentiators) rescue the protein's folding and gating — a fundamentally different strategy from degradation or enzyme replacement.
03What goes wrong
Trafficking defect + channel gating defect. The F508del mutation causes CFTR to misfold and be retained in the endoplasmic reticulum (a trafficking/folding defect), so insufficient chloride channels reach the cell surface. This is NOT a simple loss-of-function (some protein is made) nor a gain-of-function — it is a protein-folding/trafficking defect that also impairs channel gating.
04How NIGHTINGALE routes it
Recommended modality: corrector (lumacaftor/elexacaftor — rescue folding) + potentiator (ivacaftor — restore gating)
NOT eligible. CF is a trafficking/folding defect, not a toxic aggregate or a simple enzyme deficiency. Degrading CFTR would worsen the already-insufficient channel function. The correct route is small-molecule correctors (rescue folding to surface) + potentiators (restore gating) — the CFTR modulator class.
05Treatment today
Ivacaftor (Kalydeco) + elexacaftor/tezacaftor (Trikafta)
2012 (ivacaftor); 2019 (Trikafta triple combination)Ivacaftor potentiates channel gating of surface CFTR; elexacaftor/tezacaftor correct F508del folding/trafficking to the surface. Together they restore CFTR function. This is a protein-rescue strategy, not degradation or replacement.
06In the pipeline
- CFTR gene therapy (AAV/lentiviral, clinical)
- mRNA-based CFTR delivery (investigational)
- Readthrough agents (ataluren) for nonsense CFTR mutations
Key reference: PMID 23891399 · PubMed
07Verification
Every line below is the registry's own verification record — what was checked, against which source, and what is still open.
- uniprot: P13569 = CFTR, 1480 aa — VERIFIED via UniProt REST API (live)
- gene mutation: F508del (most common CFTR mutation) — VERIFIED (OMIM 219700)
- inheritance: Autosomal recessive — VERIFIED (OMIM 219700; Orphanet)
- orpha code: 586 = Cystic fibrosis (Active) — VERIFIED via Orphanet API (live, 2026-07-02)
- drug mw: 392.5 Da, CID 16220172 (ivacaftor) — VERIFIED via PubChem REST API (live)
- fda date: Ivacaftor 2012; Trikafta 2019 — commonly cited; exact NDA not re-verified this session
08Sources
| Fact | Source | Accession | Retrieved |
|---|---|---|---|
| Gene/protein identity | UniProt | P13569 (CFTR, 1480 aa) | 2026-10-04 |
| Disease classification & definition | Orphanet | ORPHAcode 586 (Cystic fibrosis) | 2026-10-04 |
| Inheritance & genetics | OMIM | 219700 (Cystic Fibrosis) | 2026-10-04 |
| Drug molecular weight (ivacaftor) | PubChem | CID 16220172 (ivacaftor, 392.5 Da) | 2026-10-04 |
Corrections carried into registry v2 (2)
- VERIFIED (2026-10-04): built fresh. ORPHAcode 586 confirmed live via Orphanet API.
- CLARIFIED: CF is a TRAFFICKING/FOLDING defect, not a simple LoF — the correct modality is corrector+potentiator (protein rescue), not degrader or enzyme replacement.