New Therapies to Correct the Cystic Fibrosis Basic Defect

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.

Keywords: CFTR; CFTR modulators; cystic fibrosis; gene therapy.

Figure 1

Role of the CFTR in the regulation of mucus viscosity and pH at the epithelial surface. Healthy mucus is composed primarily of mucins and water. Hydration and pH regulate mucus viscosity, and both of these functions are controlled by CFTR at the apical surface of epithelial cells. The movement of chloride dictates the degree to which mucus retains water whereas CFTR-mediated bicarbonate flux plays a key role in defining pH which is critical to healthy anti-bacterial response. In the absence of CFTR, secretions are viscous, adhere to mucosal surface and obstruct cylindrical structures such as small airways and sub-mucosal glands. The acidic pH further contributes to decrease host anti-bacterial defenses.

Figure 2

Classification of the CFTR disease-causing mutations. Classes I–III comprise most of the mutations associated with classical CF disease. Examples of alleles of each class are listed for each mutation class. * Class 1A is often referred to as class VII as originally suggested by De Boeck and Amaral [6].

Figure 3

Pharmacological strategies for restoring CFTR function in CF individuals with various classes of CFTR mutations. Illustrated in green are agents that increase the open probability of CFTR (potentiators), facilitate escape of misfolded protein from ERAD (correctors of class I act on NBD1, class II on NDBII and class III have an additive corrector effect in the presence of class I corrector), increase the amount of CFTR mRNA (amplifiers), increase proper translation of mRNA with PTC mutations (read-through agents), decrease NMD (NMD suppressor) and prevent degradation of CFTR protein inserted in the plasma membrane (stabilizers).