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Cystic Fibrosis Transmembrane Regulator Protein Mutations

‘Class’ Opportunity for Novel Drug Innovation

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Abstract

Cystic fibrosis (CF) is the most common autosomal, recessive, life-span shortening disease in Caucasians. Since discovery of the gene for CF (cystic fibrosis transmembrane conductance regulator [CFTR]) in 1989, knowledge of the molecular function of this gene and its interactions has offered new therapeutic targets. New therapeutics aimed at improving mutant CFTR protein function, also known as ‘protein repair therapy,’ have been proposed but are yet to be successful in clinical trials. Some of the most exciting efforts involve a new field known as small molecule discovery, which entails the identification, evaluation, and optimization of small organic compounds that can alter the function of a selected gene target or cell phenotype. More than 1300 CFTR mutations have been identified. Many of the more common mutations have been organized into five broad classes based on the fate of the mutant CFTR protein. In each of these mutation classes, interventions have been able to restore some level of CFTR function in vitro. While these ‘repairs’ have yet to be demonstrated clinically, some early clinical trials are underway. Questions regarding the amount of CFTR correction needed, delivery methods, and optimal therapeutic combinations, however, remain outstanding.

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Acknowledgements

The authors acknowledge grants from the National Institutes of Health (NHLBI) [Bethesda, MD, USA] and the Cystic Fibrosis Foundation (Bethesda, MD, USA). A licensing agreement exists between the Johns Hopkins University, Dr Zeitlin, and Ucyclyd Pharma Inc. The terms of this agreement are being managed by the Johns Hopkins University in accordance with its conflicts of interest policies.

Drs MacDonald and McKenzie have indicated they have no conflicts of interest that are directly relevant to the content of this review.

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  1. Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, 200 N. Wolfe Street, Room 3051, Baltimore, Maryland, 21287, USA

    Kelvin D. MacDonald, Karen R. McKenzie &  Pamela L. Zeitlin

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  1. Kelvin D. MacDonald
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  3. Pamela L. Zeitlin
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Correspondence to Pamela L. Zeitlin.

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MacDonald, K.D., McKenzie, K.R. & Zeitlin, P.L. Cystic Fibrosis Transmembrane Regulator Protein Mutations. Pediatr-Drugs 9, 1–10 (2007). https://doi.org/10.2165/00148581-200709010-00001

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