The response of rare CFTR mutations to specific modulator combinations

Background The combination of the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor (VX-445)–tezacaftor (VX-661)–ivacaftor (VX-770) (ETI) enables the effective rescue of CFTR function in people with the F508del mutation and 177 other US Food and Drug Administration-approved alleles. However, the effect of modulator combination treatment on many rare CFTR mutations is mostly unknown. Furthermore, rare CFTR mutations may not require all ETI components to reach maximal correction. This can be studied in intestinal organoids derived from patients carrying rare mutations. Methods Intestinal organoids were generated from six patients carrying the Q1100P and/or K163E alleles, not receiving ETI. Measurements of the response to ETI or combination of its components were performed in three-dimensional organoids by forskolin-induced swelling and in two-dimensional monolayers by short-circuit current. Based on these results, patients initiated off-label ETI treatment. Clinical data before and after treatment were collected. Results Functional measurements showed that both mutations are responsive to ETI. The results further showed that VX-445 had a dramatic effect on K163E function. Both Q1100P and K163E mutations achieved clinically significant CFTR activity levels with VX-661+VX-445, without benefit from VX-770. Following these results patients initiated off-label ETI treatment, resulting in significant and sustained clinical improvements, in all patients, in lung function (forced expiratory volume in 1 s and lung clearance index), body mass index and sweat chloride. Conclusion Our results support that CFTR function measurements in patient-derived intestinal organoids carrying rare CFTR alleles can detect potential responders to modulator treatment and serve as the basis for drug approval by health providers. Furthermore, this approach allows for patient-specific optimisation of modulator combinations, minimising unnecessary exposure to ineffective treatments.