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Small molecule drugs in cystic fibrosis
  1. Christopher Hine1,
  2. Prasad Nagakumar1,2,
  3. Maya Desai1
  1. 1 Paediatric Respiratory Medicine Department, Birmingham Children's Hospital, Birmingham, West Midlands, UK
  2. 2 Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
  1. Correspondence to Dr Christopher Hine, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK; christopher.hine{at}

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Cystic fibrosis (CF) is the most common inherited genetic disease in the Caucasian population, affecting more than 10 000 people in the UK. Discovered in 1989, the underlying pathology is a defect in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene on chromosome 7 and the subsequently produced protein. More than 2000 mutations have been identified.

Prior to the development of therapies targeting the CFTR protein, treatment has focused on preventing and treating the result of this defect including thick secretions, recurrent infections and failure to thrive. This is a significant treatment burden to the patient and family that continues lifelong.

This summary will provide an overview of small molecule precision medicines (CFTR modulators) and describe how their development is revolutionising CF care.

CFTR protein

The CFTR protein is an ATP-dependent epithelial ion channel that contributes to the absorption and secretion of salt and water in various organs including the lungs, pancreas and gastrointestinal tract. Defects in the gene for the CFTR protein leads to malfunctioning or absent CFTR protein, which in turn leads to abnormal chloride conductance on the epithelial cell apical membrane. The precise mechanism of abnormal chloride transport varies depending on the specific gene mutation. The gene mutations have historically been grouped into six classes to represent the nature of the defect (figure 1).

Figure 1

Representation of cystic fibrosis classification (I to VI). Class I—no protein: these mutations stop any recognisable CFTR protein from being produced due to stop codons in the gene. Class II—no traffic: these mutations affect CFTR processing in the endoplasmic reticulum (which recognises the malformed protein leading to protein destruction). Class III—no function: these proteins reach the cell surface, but the opening of the CFTR protein is affected. These are also called ‘gating defects’. Class IV—less function: this group of mutations reduce the passage of chloride …

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  • Contributors CH, PN and MD contributed equally.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; externally peer reviewed.

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