New and emerging targeted therapies for cystic fibrosis

Abstract

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

Fig 1 Cystic fibrosis transmembrane conductance regulator (CFTR) modulators and genetic therapies in development. Adapted, with permission, from the CF Foundation drug development pipeline

Fig 2 Diagram of the proposed structure of the cystic fibrosis transmembrane conductance regulator (CFTR) in its closed (left) and open (right) configurations. The two transmembrane spanning domains form the channel pore. Gating of the channel is controlled by the two intracytoplasmic nucleotide binding domains (NBD1 and NBD2) as they bind and hydrolyze ATP, in addition to a regulatory domain (R), which contains numerous sites of phosphorylation (P). Normal activation of the protein requires phosphorylation of the R domain. The NBDs bind and hydrolyze ATP, inducing channel gating by conferring opening of the pore through interfaces with the transmembrane domains via their extracellular loops, which also function to stabilize the protein. Cl⁻=chloride ion. Adapted from Murray and Nadel’s Textbook of Respiratory Medicine

Fig 3 CFTR mutational classes and molecular consequences. Class I mutations result in unstable truncated RNA and no synthesis of the CFTR protein. Class II mutations cause CFTR processing defects owing to misfolding of CFTR and degradation by the proteasome. Class III mutations cause reduced CFTR channel opening owing to defective channel gating or regulation. Class IV mutations cause reduced chloride conductance owing to defects within the CFTR channel. Class V mutations lead to reduced synthesis of CFTR owing to splicing defects. Class VI mutations result in reduced CFTR stability at the cell surface and hence increased CFTR turnover. The size of the inner dark circle of the CFTR channel at the apical surface reflects the extent of channel opening or conductance. CFTR=cystic fibrosis transmembrane conductance regulator; ER=endoplasmic reticulum; PTC=premature termination codon

Fig 4 Molecular basis of CFTR modulators: fate of CFTR before and after CFTR modulator treatment. Ataluren permits selective ribosomal read-through of the premature termination codon allowing the production of full length transcript and CFTR protein. Lumacaftor is capable of interacting directly with the CFTR to facilitate its correct folding or by modulating components of the cellular quality control machinery to allow proper trafficking of CFTR to the cell surface. Ivacaftor stabilizes the open state of the CFTR, thus increasing channel opening time. Areas shaded in red are the presumed targeted sites of action. The size of the inner dark circle of the CFTR channel at the apical surface reflects the extent of channel opening before and after CFTR potentiator therapy. CFTR=cystic fibrosis transmembrane conductance regulator; GA=Golgi apparatus; ER=endoplasmic reticulum; PTC=premature termination codon

Fig 5 Impact of cystic fibrosis therapies on FEV₁% predicted relative to placebo based on published clinical trial data. *Change in FEV₁% predicted not statistically significant. Note: Treatment effects are not directly comparable owing to differences in study populations and changes in standard therapy over time. CFTR=cystic fibrosis transmembrane conductance regulator; FEV₁=forced expiratory volume in one second; PA=Pseudomonas aeruginosa