Personalized therapy with CFTR modulators: Response of p.Ile148Asn variant

Area of Science:

• Molecular biology
• Genetics
• Pharmacology

Background:

• Cystic Fibrosis (CF) pathophysiology is linked to CFTR variants.
• Current CFTR modulators primarily treat common variants like p.Phe508del.
• Rare CFTR variants often lack eligibility for existing treatments, despite potential for drug rescue.

Purpose of the Study:

• To characterize the p.Ile148Asn CFTR variant in Portuguese individuals with CF.
• To assess the processing, traffic, and function of p.Ile148Asn-CFTR.
• To evaluate the response of p.Ile148Asn-CFTR to approved CFTR modulators.

Main Methods:

• Forskolin-induced swelling (FIS) assay in intestinal organoids (IOs) from CF patients.
• Generation of a Cystic Fibrosis Bronchial Epithelial (CFBE) cell line expressing p.Ile148Asn-CFTR.
• Individual molecular defect study of the p.Ile148Asn variant.

Main Results:

• The p.Ile148Asn variant causes Cystic Fibrosis by partially impairing CFTR plasma membrane traffic and function.
• p.Ile148Asn-CFTR demonstrated rescue by approved CFTR modulators in both CFBE cells and IOs.
• These findings suggest potential clinical benefits for individuals with this rare variant.

Conclusions:

• Testing CFTR modulators for rare variants not on drug labels is crucial.
• The 'theranostic' approach using patient-derived IOs complements cell line-based theratyping by considering individual genetic backgrounds.