TGFβ as a therapeutic target in cystic fibrosis

ABSTRACT

Introduction: Cystic fibrosis (CF) is a genetic disease characterized by progressive lung disease. Most CF therapies focus on treating secondary pulmonary complications rather than addressing the underlying processes inducing airway remodeling and ineffective response to infection. Transforming growth factor beta (TGFβ) is a cytokine involved in fibrosis, inflammation, and injury response as well as a genetic modifier and biomarker of CF lung disease. Targeting the TGFβ pathway has been pursued in other diseases, but the mechanism of TGFβ effects in CF is less well understood.

Areas covered: In this review, we discuss CF lung disease pathogenesis with a focus on potential links to TGFβ. TGFβ signaling in lung health and disease is reviewed. Recent studies investigating TGFβ’s impact in CF airway epithelial cells are highlighted. Finally, an overview of potential therapies to target TGFβ signaling relevant to CF are addressed.

Expert opinion: The broad impact of TGFβ signaling on numerous cellular processes in homeostasis and disease is both a strength and a challenge to developing TGFβ dependent therapeutics in CF. We discuss the challenges inherent in developing TGFβ-targeted therapy, identifying appropriate patient populations, and questions regarding the timing of treatment. Future directions for research into TGFβ focused therapeutics are discussed.

KEYWORDS:

• Cystic fibrosis
• cystic fibrosis transmembrane conductance regulator
• genetic modifier
• transforming growth factor beta

Article highlights

• TGFβ is a genetic modifier of CF lung disease and a biomarker of more severe pulmonary pathology in patients.

• TGFβ signaling drives airway remodeling, dysfunctional inflammatory responses and epithelial ion channel dysregulation in experimental models.

• The mechanism of CF disease modification by TGFβ and the utility of targeting its pathway are unknown.

• Therapeutics targeting TGFβ signaling are under development for a variety of pulmonary and non-pulmonary diseases but have not been used in CF.

• Inhibiting the TGFβ pathway in CF may improve outcomes for certain patients and allow for better efficacy of new CFTR modulating pharmaceutics.

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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 [grant number CLANCY15R0) and the National Center for Advancing Translational Sciences, National Institutes of Health [grant number KL2TR001426].