The response of rare CFTR mutations to specific modulator combinations

Area of Science:

• Genetics and Genomics
• Pharmacology and Therapeutics
• Biotechnology

Background:

• Elexacaftor-tezacaftor-ivacaftor (ETI) combination therapy effectively treats cystic fibrosis transmembrane conductance regulator (CFTR) mutations like F508del.
• The efficacy of ETI on rare CFTR mutations remains largely uncharacterized.
• Rare CFTR mutations may not necessitate all components of ETI for maximal functional correction.

Purpose of the Study:

• To investigate the efficacy of ETI and its components on rare CFTR mutations.
• To determine if patient-derived intestinal organoids can predict response to CFTR modulator therapy.
• To enable personalized optimization of CFTR modulator combinations for rare mutations.

Main Methods:

• Intestinal organoids were generated from patients with Q1100P and/or K163E CFTR mutations.
• Forskolin-induced swelling in 3D organoids and short-circuit current in 2D monolayers were used to measure response to ETI and its components.
• Off-label ETI treatment was initiated based on organoid results, with clinical data collected pre- and post-treatment.

Main Results:

• Both Q1100P and K163E mutations responded to ETI, with VX-445 showing a significant effect on K163E.
• Clinically significant CFTR activity was achieved with VX-661+VX-445 alone for both mutations, without additional benefit from VX-770.
• Patients receiving off-label ETI showed sustained improvements in lung function, body mass index, and sweat chloride levels.

Conclusions:

• CFTR function measurements in patient-derived intestinal organoids can identify potential responders to modulator therapy for rare mutations.
• This organoid-based approach can support drug approval decisions and guide personalized modulator combination selection.
• Optimizing modulator combinations minimizes patient exposure to ineffective treatments, improving therapeutic efficiency.