Transformative therapies for rare CFTR missense alleles

• Type of Material: Article
• Authors: Kathryn E. Oliver, Emory University; Sangwoo T. Han, Johns Hopkins University; Eric Sorscher, Emory University; Garry R. Cutting, Johns Hopkins University
• Language: English
• Date: 2017-06-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.coph.2017.09.018
• Title of Journal or Parent Work: Current Opinion in Pharmacology
• ISSN: 1471-4892
• Volume: 34
• Start Page: 76
• End Page: 82
• Grant/Funding Information: Support for this research was provided by R01DK44009 (NIH/NIDDK), CUTTIN15XX0 (CF Foundation) and CUTTIN16IO (CF Foundation) to GRC; P30DK072482 (NIH/NIDDK), SORSCH13XX0 (CF Foundation) and SORSCH14XX0 (CF Foundation) to EJS; and F31HL131231 (NIH/NHLBI) and OLIVER17F0 (CF Foundation) to KEO.
• Keywords: IVACAFTOR; CYSTIC-FIBROSIS; Science & Technology; Pharmacology & Pharmacy; MUTATION; EFFICACY; VARIANTS; Life Sciences & Biomedicine; TRANSMEMBRANE CONDUCTANCE REGULATOR; GENE; STEM-CELLS; IN-VITRO; MESSENGER-RNA
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology

Abstract

With over 1900 variants reported in the cystic fibrosis transmembrane conductance regulator (CFTR), enhanced understanding of cystic fibrosis (CF) genotype–phenotype correlation represents an important and expanding area of research. The potentiator Ivacaftor has proven an effective treatment for a subset of individuals carrying missense variants, particularly those that impact CFTR gating. Therapeutic efforts have recently focused on correcting the basic defect resulting from the common F508del variant, as well as many less frequent missense alleles. Modest enhancement of F508del-CFTR function has been achieved by combining Ivacaftor with Lumacaftor, a compound that aids maturational processing of misfolded CFTR. Continued development of in silico and in vitro models will facilitate CFTR variant characterization and drug testing, thereby elucidating heterogeneity in the molecular pathogenesis, phenotype, and modulator responsiveness of CF.