Strategies in early clinical development for the treatment of basic defects of cystic fibrosis

ABSTRACT

Introduction: Twenty-six years after the identification of the gene responsible for cystic fibrosis (CF), controversies still surround the pathogenesis of the disease that continues to burden and shorten lives. Therefore, finding effective therapeutic strategies that target the basic defect of CF is crucially needed.

Areas covered: This review offers a comprehensive survey of fundamental therapies in early stages of development for the treatment of CF. The first part describes recent strategies targeting the basic defect either at the gene or at the transcript level. The second part summarizes a panel of novel strategies targeting protein repair. The third part reports strategies targeting non-CFTR channels.

Expert opinion: Recent major breakthroughs in CF therapy have been made, raising hope to find a cure for CF. Apart from Vertex corrector and potentiator molecules (lumacaftor, ivacaftor, VX-661) and from ataluren, used to correct nonsense mutations, most compounds being currently tested are in very early (I-II) phases of development and definitive clinical results are keenly expected. Among the broad list of molecules and strategies being tested, the QR-010 compound and inhibitors of phosphodiesterase type 5 (sildenafil, vardenafil) could reveal a strong potentiality as therapeutic candidates to cure CF.

KEYWORDS:

• Cystic Fibrosis
• CFTR
• clinical trials
• gene therapy
• mRNA repair
• pharmacotherapy
• correctors
• potentiators
• phosphodiesterase type 5 inhibitors
• non-CFTR ion channels

Article highlights

• Targeting mRNA transcripts has recently demonstrated major advantages to treat CF disease over DNA transfection: preclinical use of QR-010, an investigational single-stranded, chemically modified RNA oligonucleotide designed to repair RNA in CF patients with the F508del mutation, resulted in translation of wild-type CFTR.

• Strategies targeting protein repair have brought significant advances to treat the basic defects of CF: the number of mutations that can be treated by ivacaftor as monotherapy has expanded and the vast majority of patients with CF is eligible for the lumacaftor–ivacaftor combotherapy, Orkambi.

• Inhibitors of phosphodiesterase 5 (sildenafil, vardenafil) are a unique group of drugs able to correct ion transport defects, to promote translocation of the protein from the near-nucleus area to the plasma membrane and to reduce exaggerated inflammatory responses in CF.

• Inhibiting exaggerated transepithelial sodium influx by blocking ENaC activity or by silencing its expression with interfering RNAs may represent therapeutic options for CF.

• Stimulating the activity of alternative non-CFTR-dependent calcium-activated chloride channels may represent another strategy to circumvent chloride transport across CF epithelia.

This box summarizes key points contained in the article.

Acknowledgements

The authors are grateful to J Lebacq (Université Catholique de Louvain) and B Schmidt (Katholieke Universiteit Leuven) for their help in editing the manuscript.

Financial and competing interests disclosure

B Dhooghe is a PhD fellow with FRIA/FNRS funds. The authors are also supported by grants from the Belgian CF Association. 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.