The revolution of personalized pharmacotherapies for cystic fibrosis: what does the future hold?

Abstract

Introduction: Cystic fibrosis (CF), a potentially fatal genetic disease, is caused by loss-of-function mutations in the gene encoding for the CFTR chloride/bicarbonate channel. Modulator drugs rescuing mutant CFTR traffic and function are now in the clinic, providing unprecedented breakthrough therapies for people with CF (PwCF) carrying specific genotypes. However, several CFTR variants are unresponsive to these therapies.

Area covered: We discussed several therapeutic approaches that are under development to tackle the fundamental cause of CF, including strategies targeting defective CFTR mRNA and/or protein expression and function. Alternatively, defective chloride secretion and dehydration in CF epithelia could be restored by exploiting pharmacological modulation of alternative targets, i.e., ion channels/transporters that concur with CFTR to maintain the airway surface liquid homeostasis (e.g., ENaC, TMEM16A, SLC26A4, SLC26A9, and ATP12A). Finally, we assessed progress and challenges in the development of gene-based therapies to replace or correct the mutant CFTR gene.

Expert opinion: CFTR modulators are benefiting many PwCF responsive to these drugs, yielding substantial improvements in various clinical outcomes. Meanwhile, the CF therapy development pipeline continues to expand with the development of novel CFTR modulators and alternative therapeutic strategies with the ultimate goal of providing effective therapies for all PwCF in the foreseeable future.

Keywords: CFTR modulators; alternative channels; correctors; drug development; gene therapy; potentiators; precision medicine; read through.

Figure 1.. CFTR Structure.

(a) the CFTR protein is comprised of five domain: two transmembrane domains (TMD1/2), two nucleotide-binding domains (NBD1/2) and a regulatory domain (RD). (b) Ribbon diagram of two views of the phosphorylated, ATP-bound conformation of CFTR (PDB: 6MSM) [11]. Only a small fraction of RD is represented since most of its structured remains undetermined due to being an intrinsically unstructured domain.

Figure 2.. CFTR Variant Classes.

Class I consists of variants that lead to no protein synthesis or translation of shortened, truncated forms. These result from abrogation of CFTR mRNA production due to mainly canonical splice sites, frameshifts, and large deletion/insertion variants (Class Ia), or nonsense variants (Class Ib), which generate premature termination codons. Class II contains variants in which the full-length protein is translated but it is misfolded and fails to achieve conformational stability, thus being recognized by endoplasmic reticulum quality control mechanisms and targeted for degradation in the proteasome. Class III consists of variants in which the protein is present at the PM but has defective channel gating due to impaired response to agonists. Class IV contains variants with reduced CFTR-dependent anion transport due to defective channel conductance. Class V consists of variants in which the number of functional CFTR channels is reduced due to reduced synthesis or inefficient protein processing. These result from alternative splicing, promoter, and missense variants. Class VI contains variants with reduced stability at the PM, thus being degraded by lysosomes due to reduced recycling or accelerated endocytosis. Variants in classes I and II are also known as minimal function variants as there is no to very little CFTR function. These variants together with those in class III are usually associated with more severe phenotypes. On the contrary, variants in classes IV, V, and VI are related to milder phenotypes as they demonstrate some CFTR function, although it is much lower than that of WT-CFTR, thus these are also known as residual function variants. Black arrows depict normal CFTR biogenesis and function, while red arrows and crosses depict defects underlying each CFTR variant class. Abbreviations: CFTR, cystic fibrosis transmembrane conductance regulator; PM, plasma membrane; WT, wild-type.

Figure 3.. Small molecule-based suppressors of CFTR nonsense variants.

Compounds that elicit greater mRNA stability and/or premature termination codon (PTC) read-through are described. A structure of the human 80S ribosome (PDB: 5LZT [96]) depicts A-, P-, and E-sites of the peptidyltransferase center, as well as binding locations of eRF1 and eRf3a. The image was generated using Chimera [97].

Figure 4.. Alternative ion channels/transporters that concur with the maintenance of airway surface liquid homeostasis.

Among the most investigated alternative targets, there are the epithelial sodium channel (ENaC) and the calcium-activated TMEM16A chloride channel, while other proteins like the SLC26A9 anion channel, the electroneutral transporters SLC26A4 (also known as pendrin) and ATP12A are emerging as targets potentially of interest.

Figure 5.. Flow-chart for the optimization of gene therapy agents.

(a) Apical or basolateral delivery of GTAs to the airway epithelium; CFTR-expressing cells color-coded according to their level of CFTR expression. (b) A proposed preclinical assessment matrix for the uniform evaluation of different GTAs in development – adapted from Dr. Foshay, NACFC ‘22∣ S21: Preclinical Assessment of Novel Genetic Therapies. Abbreviations: GTA, gene therapy agent; WT, wild-type.