CFTR modulator theratyping: Current status, gaps and future directions.

Area of Science:

• Biomedical research
• Genetics
• Pharmacology

Background:

• New drugs targeting cystic fibrosis transmembrane conductance regulator (CFTR) protein variants have advanced cystic fibrosis (CF) treatment.
• Preclinical models are crucial for understanding CFTR defects and exploring modulator therapies for rare variants.

Purpose of the Study:

• To discuss the utility of preclinical models in characterizing CFTR variants.
• To explore the role of in vitro CFTR modulator testing for informing in vivo modulator use.
• To focus on CFTR theratyping for defining CFTR defects and guiding therapy for common and rare variants.

Main Methods:

• A workshop convened international experts to discuss preclinical CFTR model systems and in vitro modulator testing.
• CFTR theratyping was defined as using CFTR modulators to characterize CFTR defects in vitro.
• Model systems evaluated included cell lines and patient-derived cells from various tissues.

Main Results:

• Various preclinical model systems for CFTR variant analysis were identified, with differing levels of maturity.
• Key considerations for model systems include standardization, validation, and predictive capacity for clinical outcomes.
• Data from these models can help estimate patient responses to modulator therapies.

Conclusions:

• CFTR modulator theratyping is an emerging field with significant potential.
• This approach can identify rare CFTR variants that may benefit from approved or investigational modulator drugs.