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Targeted Therapy for Cystic Fibrosis

Cystic Fibrosis Transmembrane Conductance Regulator Mutation-Specific Pharmacologic Strategies

  • Genetic Disorders
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Abstract

Cystic fibrosis (CF) results from the absence or dysfunction of a single protein, the CF transmembrane conductance regulator (CFTR). CFTR plays a critical role in the regulation of ion transport in a number of exocrine epithelia. Improvement or restoration of CFTR function, where it is deficient, should improve the CF phenotype. There are >1000 reported disease-causing mutations of the CFTR gene. Recent investigations have afforded a better understanding of the mechanism of dysfunction of many of these mutant CFTRs, and have allowed them to be classified according to their mechanism of dysfunction. These data, as well as an enhanced understanding of the role of CFTR in regulating epithelial ion transport, have led to the development of therapeutic strategies based on pharmacologic enhancement or repair of mutant CFTR dysfunction. The strategy, termed ‘protein repair therapy’, is aimed at improving the regulation of epithelial ion transport by mutant CFTRs in a mutation-specific fashion. The grouping of CFTR gene mutations, according to mechanism of dysfunction, yields some guidance as to which pharmacologic repair agents may be useful for specific CFTR mutations. Recent data has suggested that combinations of pharmacologic repair agents may be necessary to obtain clinically meaningful CFTR repair. Nevertheless, such strategies to improve mutant CFTR function hold great promise for the development of novel therapies aimed at correcting the underlying pathophysiology of CF.

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Acknowledgments

The author’s research is supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers R01–DK58046 and R01–DK54354), the Cystic Fibrosis Foundation, and an Established Investigator Award from the American Heart Association.

The author has no conflict of interest that is directly relevant to the content of this review.

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  1. Division of Pulmonary Medicine and Cystic Fibrosis Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Ronald C. Rubenstein

  2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Ronald C. Rubenstein

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Rubenstein, R.C. Targeted Therapy for Cystic Fibrosis. Mol Diag Ther 10, 293–301 (2006). https://doi.org/10.1007/BF03256204

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