Cystic Fibrosis: Gene Therapy


Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations of the CFTR gene, which encodes a member of the adenosine triphosphate‐binding cassette superfamily of transmembrane proteins. CFTR normally acts as a cyclic adenosine monophosphate‐activated chloride channel and as a regulator of other ion channels. The main cause of morbidity and mortality is the effect of CFTR dysfunction on the lung, which reduces life expectancy of CF patients (current median approximately 40 years according to UK and US national patient registries). There has been some progress in the identification of pharmacological agents that can correct the CFTR defect in patients carrying some classes of mutation, but with nearly 2000 different disease‐causing mutations reported, gene therapy remains the most likely option for the amelioration of lung disease in the majority of CF sufferers. The progress achieved and the hurdles identified as a result of the clinical trials of gene therapy vectors in CF patients are reviewed.

Key Concepts:

  • CF is a monogenic recessive disease with an incidence of 1:2500 in populations of Caucasian descent in particular, caused by mutations in the CFTR gene.

  • It is a life‐limiting condition and disease management involves a heavy therapeutic burden with no definitive cure.

  • Disruption of the CFTR gene leads to incorrect or insufficient transport of chloride ions across the epithelial cells of the body with a range of consequences in different organs, crucially inadequate clearance of bacteria from the lungs due to ineffective mucociliary clearance, resulting in progressive fibrosis and clogging of the lung with mucus, and eventually respiratory failure.

  • Discovery of the genetic basis for CF quickly led to evaluation of gene therapy as a therapeutic option, with a range of viral and nonviral vectors.

  • Although the vectors tested showed some efficacy in terms of correcting the fundamental chloride transport defect, no CF gene therapy trial has so far been able to demonstrate long‐term clinical improvement.

Keywords: gene therapy; clinical trials; lung; cystic fibrosis; nonviral; gene transfer agent; viral vectors

Figure 1.

Schematic representation of CFTR biosynthesis, CF‐causing mutations and pharmacological interventions under investigation. Biosynthesis of CFTR, shown on left‐hand side, involves translation of the spliced mRNA in the endoplasmic reticulum (ER) with concomitant chaperone‐dependent folding, export through the Golgi for post‐translational maturation (complex glycosylation), and transport to the membrane in clathrin‐coated vesicles for insertion into the apical membrane. There, CFTR channel opening is regulated by ATP hydrolysis at NBD1 and 2, as well as phosphorylation of the R domain, and eventually CFTR is either recycled or degraded via the lysosomal and/or ubiquitin‐dependent degradation pathways (Rogan et al., ). The apical and basolateral surfaces are separated by the tight junctions indicated in orange. Channels that also contribute to the balance of salt and water across the apical membrane include calcium‐activated chloride channel (CaCC) and epithelial sodium channel (ENaC). The middle section outlines how CF‐causing mutations can affect the different steps in CFTR biosynthesis. The most common CF allele, F508del, produces a class II mutant with increased degradation of the misfolded protein in the ER or the Golgi (other examples include N1303K, G85E); class I mutations (∼10% of all CF mutations) typically involve early termination of transcription especially due to premature stop codons (e.g. G542X, W1282X); class III and class IV mutants encode correctly folded and apically‐localised CFTR that, respectively, has gating defects or is aberrantly regulated (∼2–3% of all CF mutations, e.g. G551D, R560T) and conductance defects (<2% of all CF mutations, e.g. R117H, R347P); class V mutants typically affect the rate of synthesis of CFTR protein that is otherwise normal, leading to a reduction in chloride transport (<1% of all CF mutations, e.g. 2849+10kbC→T; 2789+5G→A) (O'Sullivan and Freedman, ; Rogan et al., ; Pettit, ). The right‐hand panel shows the types of drug molecules under investigation, which may be able to improve ion balance across the respiratory epithelium, by improving expression, translation, maturation, and channel properties of the various CFTR mutants, or interfere with excessive sodium transport from the airway surface through ENaC (Ong and Ramsey, ; Rowe and Verkman, ).



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Web Links

Cystic Fibrosis Mutation Database, Statistics (accessed on 10 Nov 2013).

Cystic Fibrosis Transmembrane Conductance Regulator, ATP‐Binding Cassette (Sub‐family C, Member 7) (CFTR); MIM: 602421. GeneLink.

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Sumner‐Jones, Stephanie G, and Gill, Deborah R(Apr 2014) Cystic Fibrosis: Gene Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005749.pub2]