Gene Therapy for Human Disease: Clinical Advances and Challenges
Review Article
Gene therapy in cystic fibrosis

https://doi.org/10.1016/j.trsl.2012.12.001Get rights and content

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene and is the most common life-shortening genetic defect in Caucasians. Life expectancy in CF has improved substantially over the last 75 years because of treatments aimed at end-organ complications. Since the CFTR gene was discovered in 1989 more than 1900 mutations have been reported to cause CF and significant effort has been put forth into gene therapy to find a mutation independent “cure” for CF. Gene-based approaches have not yet led to a viable therapy but have provided insights into hurdles that limit the efficacy of gene therapy. This review will address the nomenclature of CFTR mutations, attempts at viral and nonviral gene therapy, and recent advances in mutation-specific molecules.

Section snippets

A Brief History of Cystic Fibrosis Genetics

Recognition of characteristic cystic fibrosis (CF) symptoms and their relationship to mortality has existed for centuries. References in medieval folklore spoke of premature death for an infant that tastes “salty”.1 Alonso y de los Ruyzes de Fonteca, professor of medicine at Henares in Spain, wrote that it was known that fingers tasted salty after rubbing the forehead of a bewitched child.2 Subsequently, various other reports associated defective pancreatic function with steatorrhea and

CFTR Mutation Nomenclature

As the numbers of genetic mutations in CFTR continues to expand, it has become increasingly important to categorize mutations based on the protein defect caused by specific mutations. There have been 5 functional classes of CFTR mutations defined, each acting at a different stage of protein synthesis (Table I).15 Mutations belonging to class I–III have little to no functional CFTR production typically leading to more severe or classic CF phenotypes. Class I mutations produce biosynthetic

Gene Therapy Advances–Slowly but Surely

Since the identification of the mutant CFTR gene as the cause of CF there has been a significant effort to harness gene therapy to correct the mutation at a cellular level. Traditional gene therapy would aim to place a copy of normal CFTR into the patients cells. The power of this approach is that it could potentially be curative for all CF patients regardless of the genotype. Despite the theoretical allure of gene therapy, the reality of bringing this technology to the clinical setting has

Mutant Protein Repair

After the discovery of the gene, CFTR was identified as a member of the traffic ATPase family and a chloride channel.10, 11, 58 Subsequently, it was shown to transport other anions (eg, thiocyanate and bicarbonate), and to regulate ion transporters such as the epithelial sodium channel and alternative chloride channels.59, 60, 61, 62 This work provided a new perspective for relationships between CFTR mutations and the molecular mechanism of their associated dysfunction. The breakdown of

CFTR Potentiators

Potentiators are CFTR modulators that increase the time CFTR spends in the open channel configuration, with increased chloride transport. Ivacaftor, the first potentiator to gain Food and Drug Administration approval is used for CF patients with the G551D mutation.63 Though it is the second most common mutation identified as a cause of CF, G551D is present in only about 4% of CF patients.13 Ivacaftor has been studied in one phase II67 and 2 pivotal phase III trials,68 (NCT00909727). In all 3

PTC Mutation Suppressors

PTCs result when single base-pair substitutions create an erroneous stop codon within the open reading frame of a gene. Suppressors of PTCs, such as aminoglycoside antibiotics, are able to bind eukaryotic ribosomes and cause the insertion of a near cognate amino-acyl transfer RNA into the ribosomal A site.71 This process can allow the ribosome to ‘readthrough’ the PTC and produce some full length protein and has been extensively tested in proof of concept studies utilizing aminoglycosides to

CFTR Correctors

The F508del mutation disrupts folding of nascent CFTR, causing retention in the endoplasmic reticulum and subsequent proteasomal degradation.62 The result is minimal protein escaping intracellular degradation. CFTR correctors increase F508del CFTR protein at the plasma membrane, and Vertex Pharmaceuticals has developed 2 F508del correctors that have advanced to clinical trials. One F508del CFTR corrector (VX-809; Lumacaftor) has been assessed in a phase 2, multicenter, randomized, double blind,

Conclusion

The discovery that mutant CFTR is the cause of CF engendered hope that gene therapy would lead to a disease cure. Although there has been substantial work toward this goal, the hope remains unrealized more than 20 years later. Much has been learned in the intervening period with respect to hurdles and limitations of gene therapy. Newer approaches targeting repair of mutant CFTR proteins are a promising alternative to gene therapy. Nevertheless, work continues in trying to identify the optimal

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    Conflict of interest: All authors have read the journal’s policy on conflicts of interest and have none to declare.

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