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:

• alternative channels
• CFTR modulators
• correctors
• drug development
• gene therapy
• potentiators
• precision medicine
• read through

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.

Additional information

Funding

Work of K.E. Oliver is supported by the U.S. National Institutes of Health (R00HL151965) and the U.S. Cystic Fibrosis Foundation (OLIVER22A0-KB). Work of M.S. Carlon is supported by the Belgian Cystic Fibrosis Association & King Baudouin Foundation Fund Forton (2020-J1810150-E015) and an Emily’s Entourage grant (US_172749169_6). Work of N. Pedemonte is supported by the Fondazione per la Ricerca sulla Fibrosi Cistica grant FFC #10/2021 (with the contribution of “Delegazione FFC di Genova”, “Gruppo FC Altomilanese”, “Gruppo di sostegno FFC Ricerca di Campiglione Fenile”, and “Delegazione FFC Ricerca di Napoli”), the Cystic Fibrosis Foundation (PEDEMO20G0), and the Italian Ministry of Health through Cinque per mille and Ricerca Corrente. Work of M. Lopes-Pacheco is supported by the U.S. Cystic Fibrosis Foundation (LOPES21I0 and LOPES23G0) and the 2020 center grant from FCT Portugal (UIDB/04046/2020 and UIDP/04047/2020 to BioISI).