Cystic Fibrosis: Proteostatic correctors of CFTR trafficking and alternative therapeutic targets.

ABSTRACT

Introduction: Cystic fibrosis (CF) is the most frequent lethal orphan disease and is caused by mutations in the CFTR gene. The most frequent mutation F508del-CFTR affects multiple organs; infections and subsequent infections and complications in the lung lead to death.

Areas covered: This review focuses on new targets and mechanisms that are attracting interest for the development of CF therapies. The F508del-CFTR protein is retained in the endoplasmic reticulum (ER) but has some function if it can traffic to the plasma membrane. Cell-based assays have been used to screen chemical libraries for small molecule correctors that restore its trafficking. Pharmacological chaperones are correctors that bind directly to the F508del-CFTR mutant and promote its folding and trafficking. Other correctors fall into a heterogeneous class of proteostasis modulators that act indirectly by altering cellular homeostasis.

Expert opinion: Pharmacological chaperones have so far been the most successful correctors of F508del-CFTR trafficking, but their level of correction means that more than one corrector is required. Proteostasis modulators have low levels of correction but hold promise because some can correct several different CFTR mutations. Identification of their cellular targets and the potential for development may lead to new therapies for CF.

KEYWORDS:

• Proteostasis modulators
• cystic fibrosis
• protein trafficking
• quality control

Article Highlights

• Functional expression of CFTR mutants can be increased by small molecules called correctors.

• Proteostasis modulator-type correctors act indirectly through diverse pathways to increase the folding and/or trafficking of mutant CFTR.

• New corrector compounds have been identified by cell-based high throughput screening but their targets are surprisingly diverse.

• The targets and mechanisms of action of some of these correctors are critically assessed.

• Interest in non-CFTR targets is increasing as incremental improvements provided by new CFTR modulators decline.

This box summarizes key points contained in the article.

Declaration of interest

DY Thomas is a Canada Research Chair (Tier 1) and is a cofounder and shareholder in Traffick Therapeutics Inc. J.W. Hanrahan is a cofounder and shareholder in Traffick Therapeutics Inc. DY Thomas and JW Hanrahan have also received research funding from GSK plc and Verona Pharma plc, have served as consultants for Vertex Pharmaceuticals Inc. and ERAD Therapeutics Inc., and hold patents with Verona and Laurent Pharmaceuticals Inc. 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. 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

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The research of the authors is supported by grants from Cystic Fibrosis Canada [awarded to J Hanrahan and DY Thomas] and the Canadian Institutes of Health Research [awarded to JC Young, JW Hanrahan and DY Thomas, MOP −119341].