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Genome Medicine

, 7:101

First Online: 24 September 2015

Abstract

Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator CFTR gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.

AbbreviationsASLAirway surface liquid

BMIBody mass index

CBFCiliary beat frequency

CFCystic fibrosis

CFQ-RRevised cystic fibrosis questionnaire

EC50half-maximum effective concentration

FDAFood and Drug Administration

FEV1Baseline forced expiratory volume in 1 second

HBEHuman bronchial epithelial cell

kbKilobases

LCIlung clearance index

PTCPremature termination codon

RCTRandomized controlled trial

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Author: Malcolm Brodlie - Iram J. Haq - Katie Roberts - J. Stuart Elborn

Source: https://link.springer.com/







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