Abstract
Rare diseases affect 400 million individuals worldwide and cause significant morbidity and mortality. Finding solutions for rare diseases can be very challenging for physicians and researchers. Cystic fibrosis (CF), a genetic, autosomal recessive, multisystemic, life-limiting disease does not escape this sad reality. Despite phenomenal progress in our understanding of this disease, treatment remains difficult. Until recently, therapies for CF individuals were focused on symptom management. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its product, a protein present at the apical surface of epithelial cells regulating ion transport, allowed the scientific community to learn about the basic defect in CF and to study potential therapies targeting the dysfunctional protein. In the past few years, promising therapies with the goal to restore CFTR function became available and changed the lives of several CF patients. These medications, called CFTR modulators, aim to correct, potentialize, stabilize or amplify CFTR function. Furthermore, research is ongoing to develop other targeted therapies that could be more efficient and benefit a larger proportion of the CF community. The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, particularly CFTR modulators and gene therapy.
Highlights
Cystic fibrosis (CF) has evolved from a fatal disease of unknown cause to a condition we understand with molecular precision [1]
The purpose of this review is to summarize our current knowledge of CF genetics and therapies restoring CFTR function, CFTR modulators and gene therapy
In vitro data from rigorously controlled assays in Fisher rat thyroid (FRT) cells expressing rare CFTR mutations has become an important step in meeting regulatory requirements for approval of drugs that could help individuals with CF-causing gating mutations not addressed in clinical trials [60]
Summary
Cystic fibrosis (CF) has evolved from a fatal disease of unknown cause to a condition we understand with molecular precision [1]. Class I includes frameshift, splicing and non-sense mutations that result in incomplete or absent mRNA and no functional CFTR protein synthesis. The little amount of F508del CFTR protein that makes it to the membrane has a severe class III gating defect and is unstable at the apical membrane (class VI) [11]. The most common mutation in this class is R117H This mutation produces a gating (class III) defect which can be partially rescued by potentiator therapy with ivacaftor [19]. Class V mutations result in greatly reduced amounts of functional CFTR at the apical membrane due to promoter mutations, alternate splicing defects or missense mutations resulting in abnormal mRNA transcripts [20]. Classes of CFTR modulating agents include potentiators, correctors, amplifiers, read-through agents, NMD suppressors and stabilizers
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