Discovery of CFTR modulators for the treatment of cystic fibrosis

ABSTRACT

Introduction

Cystic fibrosis (CF) is a life-threatening inherited disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, an anion channel expressed at the apical membrane of secretory epithelia. CF leads to multiorgan dysfunction with progressive deterioration of lung function being the major cause of untimely death. Conventional CF therapies target only symptoms and consequences downstream of the primary genetic defect and the current life expectancy and quality of life of these individuals are still very limited.

Area covered

CFTR modulator drugs are novel-specialized therapies that enhance or even restore functional expression of CFTR mutants and have been approved for clinical use for individuals with specific CF genotypes. This review summarizes classical approaches used for the pre-clinical development of CFTR correctors and potentiators as well as emerging strategies aiming to accelerate modulator development and expand theratyping efforts.

Expert opinion

Highly effective CFTR modulator drugs are expected to deeply modify the disease course for the majority of individuals with CF. A multitude of experimental approaches have been established to accelerate the development of novel modulators. CF patient-derived specimens are valuable cell models to predict therapeutic effectiveness of existing (and novel) modulators in a precision medicine approach.

KEYWORDS:

• Cell models
• cftr mutations
• correctors
• drug discovery
• potentiators
• personalized therapies
• precision medicine
• theratyping

Article Highlights

• Different CFTR modulator therapies are required for CFTR mutants with distinct primary defects.

• Unraveling the mechanisms of action of individual modulators will aid in selecting combinations with additive/synergistic actions to increase clinical outcomes.

• In vitro studies have been useful in extending the label of approved modulator therapies for rare and ultra-rare CFTR mutations.

• A multitude of novel approaches have been developed to circumvent barriers and accelerate the discovery of novel modulator drugs.

• Patient-derived specimens are valuable tools for precision medicine application.

• Highly effective CFTR modulator therapies are available for clinical use and are expected to deeply modify the disease course for the majority of individuals with CF.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.