BACKGROUND: For most of the >2000 CFTR gene variants reported, neither the associated disease liability nor the underlying basic defect are known, and yet these are essential for disease prognosis and CFTR-based therapeutics. Here we aimed to characterize two ultra-rare mutations - 1717-2A > G (c.1585-2A > G) and S955P (p.Ser955Pro) - as case studies for personalized medicine. METHODS: Patient-derived rectal biopsies and intestinal organoids from two individuals with each of these mutations and F508del (p.Phe508del) in the other allele were used to assess CFTR function, response to modulators and RNA splicing pattern. In parallel, we used cellular models to further characterize S955P independently of F508del and to assess its response to CFTR modulators. RESULTS: Results in both rectal biopsies and intestinal organoids from both patients evidence residual CFTR function. Further characterization shows that 1717-2A > G leads to alternative splicing generating <1% normal CFTR mRNA and that S955P affects CFTR gating. Finally, studies in organoids predict that both patients are responders to VX-770 alone and even more to VX-770 combined with VX-809 or VX-661, although to different levels. CONCLUSION: This study demonstrates the high potential of personalized medicine through theranostics to extend the label of approved drugs to patients with rare mutations.

• Keywords
• CFTR modulators, Intestinal organoids, Precision medicine, Rare mutations, Theranostics,
• MeSH
• Alleles MeSH
• Aminophenols therapeutic use   MeSH
• Aminopyridines therapeutic use   MeSH
• Benzodioxoles therapeutic use   MeSH
• Quinolones therapeutic use   MeSH
• Cystic Fibrosis drug therapy   genetics   MeSH
• Electrophysiology MeSH
• Fluorescent Antibody Technique MeSH
• Genotype MeSH
• Precision Medicine methods   MeSH
• Indoles therapeutic use   MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aminophenols MeSH
• Aminopyridines MeSH
• Benzodioxoles MeSH
• Quinolones MeSH
• Indoles MeSH
• ivacaftor MeSH Browser
• lumacaftor MeSH Browser
• Cystic Fibrosis Transmembrane Conductance Regulator MeSH
• tezacaftor MeSH Browser

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

• Keywords
• CFTR modulators, Clinical trials, Drug development, Global perspective,
• MeSH
• Cystic Fibrosis drug therapy   genetics   MeSH
• Humans MeSH
• International Cooperation * MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator drug effects   MeSH
• Drug Development organization & administration   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• CFTR protein, human MeSH Browser
• Cystic Fibrosis Transmembrane Conductance Regulator MeSH