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.
Article highlights
Despite the therapeutic success of clinically approved CFTR modulators, they are unable to completely restore CFTR protein stability and traffic defects as well as channel gating activity for various variants, including G551D and F508del.
A considerable number of novel correctors and potentiators has been identified but their mechanism of action (MoA) remains poorly elucidated.
Recent evidence suggests that at least three MoA’s exist for CFTR potentiation and they can be targeted simultaneously to maximize CFTR gating activity.
Strategies to mitigate nonsense-mediated mRNA decay are likely to be necessary to increase transcript levels available for subsequent protein translation and read-through activity.
Mutation location, surrounding nucleotides, codon identity, and other sequence features should be considered when developing therapeutic strategies for CFTR nonsense alleles.
Defective chloride secretion and epithelial dehydration could be restored by exploiting the pharmacological modulation of alternative targets.
Preclinical evidence shows the feasibility of gene-based approaches relying on supplementation of CFTR cDNA or mRNA in a variant-agnostic manner or insertion of super-exons.
CRISPR-Cas-based gene editing and its derivatives collectively have theoretical applicability to correct up to 93% of CF-causing variants.
Abbreviation
ABC, | = | ATP-binding cassette; |
ANKZF1, | = | ankyrin repeat and zinc finger peptidyl tRNA hydrolase 1; |
ASL, | = | airway surface liquid; |
ATP, | = | adenosine triphosphate; |
CaCC, | = | calcium-activated chloride channel; |
cDNA, | = | complementary DNA; |
CF, | = | cystic fibrosis; |
CFTR, | = | CF transmembrane conductance regulator; |
Cryo-EM, | = | cryogenic electron microscopy; |
ECL, | = | extracellular loop; |
ENaC, | = | epithelial sodium channel; |
ETI, | = | elexacaftor/tezacaftor/ivacaftor; |
FRT, | = | Fischer rat thyroid; |
GTA, | = | gene therapy agent; |
GTPBP2, | = | GTP-binding protein 2; |
HBS1L, | = | HBS1-like translational GTPase; |
ICL, | = | intracellular loop; |
IL, | = | interleukin; |
LTN1, | = | listerin E3 ubiquitin ligase 1; |
MoA, | = | mechanism of action; |
mRNA, | = | messenger RNA; |
NB, | = | nucleotide-binding domain; |
NEMF, | = | nuclear export mediator factor; |
NMD, | = | nonsense-mediated decay; |
PKA, | = | protein kinase A; |
PM, | = | plasma membrane; |
PwCF, | = | people with CF; |
PTC, | = | premature termination codon; |
R, | = | regulatory; |
SMG, | = | suppressors with morphogenetic effects on genitalia; |
SORT, | = | selective organ targeting; |
TCF25, | = | transcription factor 25; |
TMD, | = | transmembrane domain; |
TNF, | = | tumor necrosis factor; |
tRNA, | = | transfer RNA; |
UPF, | = | up-frameshift; |
VCP, | = | valosin-containing protein; |
WT, | = | wild-type; |
ZNF598, | = | zinc finger protein 598. |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer declarations
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.