Gene Therapy for Human Disease: Clinical Advances and ChallengesReview ArticleGene therapy in cystic fibrosis
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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2021, Advanced Drug Delivery ReviewsCitation Excerpt :Among lung genetic disorders, the most common chronic and life-threatening one is cystic fibrosis (CF) caused by single gene defects [1]. Apart from CF, α-1 antitrypsin deficiency (AATD) also represents one of most common genetic disorders, particularly in North America [2]. Other lung genetic-related disorders including lung cancer, asthma, and chronic obstructive pulmonary disease (COPD) are also life-threatening diseases which are yet short of effective treatment options.
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2016, Journal of Controlled ReleaseCitation Excerpt :They concluded that a more potent gene delivery vector is required to make gene therapy a viable option for treating CF [33]. Clinical trials for CF gene therapy have shown evidence of CFTR transgene expression based on measurements of CFTR mRNA and changes in nasal potential difference (NPD), but no significant improvement in lung function parameters has been reported [34,35]. This suggests that the levels of gene transfer achieved in clinical trials have been insufficient to mediate a functional cure in the CF airways.
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Conflict of interest: All authors have read the journal’s policy on conflicts of interest and have none to declare.