CFTR functional assays in drug development

ABSTRACT

Introduction: Cystic Fibrosis (CF) is the most common fatal genetic disease in persons of Northern European ancestry. It is an autosomal recessive disease caused by loss of function of the cystic fibrosis transmembrane conductance regulator protein (CFTR), a transmembrane chloride and bicarbonate channel. Traditional management of CF targets symptoms, while recently developed therapies (modulators) directly improve CFTR function.

Areas covered: This article highlights in vitro methods that have broadened the understanding of CFTR structure and function and led to the development of CFTR modulators, in vivo methods to clinically assess CFTR function and modulation, and ex vivo methods that directly evaluate CFTR activity in specific cell types. Focus will be placed on how these assays bring new drugs from initial discovery to patient use.

Expert opinion: Use of currently available CFTR assays from the lab to the patient and back will empower a robust program of drug discovery and expansion across CF patients with both common and rare CFTR mutations. This capacity exists, but requires optimization and integration to be fully realized. The ability to measure drug bioactivity at the protein level across numerous systems represents an unprecedented opportunity to further care of patients with CF.

KEYWORDS:

• Cystic fibrosis
• CFTR
• sweat chloride
• drug development

Article highlights

• The emergence of CFTR modulation as a therapy for CF has been empowered by multiple assays of CFTR function

• Human and heterologous in vitro systems advance biochemical understanding of CFTR dysfunction and allow high-throughput compound screening

• Sweat chloride and nasal potential difference are in vivo assays that reliably demonstrate drug bioactivity on CFTR function

• Ex vivo models derived from patient tissues are an untapped resource for drug development and optimization, potentially at the patient level

• Optimization and integration of CFTR functional assays will promote a cycle of efficient drug discovery, validation, and expansion towards improving CFTR function and outcomes in all patients 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the Cystic Fibrosis Foundation under grants BREWIN16A0, CLANCY15R0, and ZAK15B0.