Modulating the cystic fibrosis transmembrane regulator and the development of new precision drugs

ABSTRACT

Introduction: Thirty years after the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene discovery, we are now witnessing the wind of change with the development of second generation modulators targeting CFTR after the successful marketing of the first precision medicaments.

Areas covered: This review discusses the therapeutic options targeting CFTR maturation and activity and highlight the need to better define the effects of mutations on CFTR biology, using a multiclass classification. The contribution of new patient-derived cellular models to the development of precision medicine will also be discussed.

Expert commentary: Despite the pursuit of numerous strategies for combating the disease, development of successful therapies has proved to be very challenging given the complexity of this genetic disorder. The first-in-class drugs now prescribed to CF individuals are not only too expensive but also not as efficacious as hoped despite in-depth in vitro investigation. Therefore, among the current challenges we are facing, are the need of better animal and model systems, novel strategies to discover more potent combinations of drugs to efficiently alleviate CF defects and the need to better classify CF mutations (in particular rare and very rare CFTR mutations) to take into account the multiple defects of the mutated CFTR protein.

KEYWORDS:

• CFTR
• precision medicine
• classification of CF mutations

Declaration of interest

Research in F Becq’s laboratory is supported by Vaincre La Mucoviscidose, Mucovie66, ABCF2 Amandine contre la Mucoviscidose. A Billet is supported by a postdoctoral SRC grant from UK CF trust (SRC005). L Froux is supported by a postdoctoral grant from Vaincre La Mucoviscidose. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper has not been funded.