One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Jun 24

PMID 35740997

Authors

Marjolein M Ensinck

Marianne S Carlon

Affiliations

Soon will be listed here.

Abstract

Cystic fibrosis (CF) is the most common monogenic disorder, caused by mutations in the CF transmembrane conductance regulator () gene. Over the last 30 years, tremendous progress has been made in understanding the molecular basis of CF and the development of treatments that target the underlying defects in CF. Currently, a highly effective CFTR modulator treatment (Kalydeco™/Trikafta™) is available for 90% of people with CF. In this review, we will give an extensive overview of past and ongoing efforts in the development of therapies targeting the molecular defects in CF. We will discuss strategies targeting the CFTR protein (i.e., CFTR modulators such as correctors and potentiators), its cellular environment (i.e., proteostasis modulation, stabilization at the plasma membrane), the mRNA (i.e., amplifiers, nonsense mediated mRNA decay suppressors, translational readthrough inducing drugs) or the gene (gene therapies). Finally, we will focus on how these efforts can be applied to the 15% of people with CF for whom no causal therapy is available yet.

Citing Articles

Endometrium-derived organoids from cystic fibrosis patients and mice as new models to study disease-associated endometrial pathobiology.

De Pauw E, Gommers B, Ensinck M, Timmerman S, De Vriendt S, Bueds C Cell Mol Life Sci. 2025; 82(1):109.

PMID: 40074868 PMC: 11904040. DOI: 10.1007/s00018-025-05627-7.

DNA-PKcs inhibition improves sequential gene insertion of the full-length cDNA in airway stem cells.

Stack J, Rayner R, Nouri R, Suarez C, Kim S, Kanke K Mol Ther Nucleic Acids. 2024; 35(4):102339.

PMID: 39398224 PMC: 11470261. DOI: 10.1016/j.omtn.2024.102339.

DNA-PKcs Inhibition Improves Sequential Gene Insertion of the Full-Length cDNA in Airway Stem Cells.

Stack J, Rayner R, Nouri R, Suarez C, Kim S, Kanke K bioRxiv. 2024; .

PMID: 39185207 PMC: 11343149. DOI: 10.1101/2024.08.12.607571.

Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy.

Moiseenko A, Sinadinos A, Sergijenko A, Pineault K, Saleh A, Nekola K Eur Respir J. 2024; 65(1).

PMID: 39174284 PMC: 11780724. DOI: 10.1183/13993003.01683-2023.

Beyond the 10%: Unraveling the genetic diversity in Turkish cystic fibrosis patients not eligible for CFTR modulators.

Yildiz C, Selcuk Balci M, Karabulut S, Baser Z, Yuksel Kalyoncu M, Metin Cakar N Pediatr Pulmonol. 2024; 59(12):3250-3259.

PMID: 39031495 PMC: 11601005. DOI: 10.1002/ppul.27181.

References

Leubitz A, Frydman-Marom A, Sharpe N, van Duzer J, Campbell K, Vanhoutte F . Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of ELX-02, a Potential Treatment for Genetic Disorders Caused by Nonsense Mutations, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019; 8(8):984-994. DOI: 10.1002/cpdd.647. View

Valley H, Bukis K, Bell A, Cheng Y, Wong E, Jordan N . Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells. J Cyst Fibros. 2018; 18(4):476-483. DOI: 10.1016/j.jcf.2018.12.001. View

Liu F, Zhang Z, Csanady L, Gadsby D, Chen J . Molecular Structure of the Human CFTR Ion Channel. Cell. 2017; 169(1):85-95.e8. DOI: 10.1016/j.cell.2017.02.024. View

Becq F, Mettey Y, Gray M, Galietta L, Dormer R, Merten M . Development of substituted Benzo[c]quinolizinium compounds as novel activators of the cystic fibrosis chloride channel. J Biol Chem. 1999; 274(39):27415-25. DOI: 10.1074/jbc.274.39.27415. View

Botelho H, Uliyakina I, Awatade N, Proenca M, Tischer C, Sirianant L . Protein traffic disorders: an effective high-throughput fluorescence microscopy pipeline for drug discovery. Sci Rep. 2015; 5:9038. PMC: 4356983. DOI: 10.1038/srep09038. View

Loureiro C, Pinto F, Barros P, Matos P, Jordan P . A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane. Cell Mol Life Sci. 2020; 77(23):4997-5015. PMC: 11105000. DOI: 10.1007/s00018-020-03448-4. View

Lansdell K, Cai Z, Kidd J, Sheppard D . Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in murine cell line. J Physiol. 2000; 524 Pt 2:317-30. PMC: 2269882. DOI: 10.1111/j.1469-7793.2000.t01-1-00317.x. View

Carlile G, Robert R, Zhang D, Teske K, Luo Y, Hanrahan J . Correctors of protein trafficking defects identified by a novel high-throughput screening assay. Chembiochem. 2007; 8(9):1012-20. DOI: 10.1002/cbic.200700027. View

Lubamba B, Lecourt H, Lebacq J, Lebecque P, de Jonge H, Wallemacq P . Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis. Am J Respir Crit Care Med. 2007; 177(5):506-15. DOI: 10.1164/rccm.200703-344OC. View

10.

Clancy J, Rowe S, Bebok Z, Aitken M, Gibson R, Zeitlin P . No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations. Am J Respir Cell Mol Biol. 2007; 37(1):57-66. PMC: 1899350. DOI: 10.1165/rcmb.2006-0173OC. View

11.

Gonzalez-Hilarion S, Beghyn T, Jia J, Debreuck N, Berte G, Mamchaoui K . Rescue of nonsense mutations by amlexanox in human cells. Orphanet J Rare Dis. 2012; 7:58. PMC: 3562214. DOI: 10.1186/1750-1172-7-58. View

12.

Riordan J, Rommens J, Kerem B, Alon N, Rozmahel R, Grzelczak Z . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989; 245(4922):1066-73. DOI: 10.1126/science.2475911. View

13.

Huang Y, Paul G, Lee J, Yarlagadda S, McCoy K, Naren A . Elexacaftor/Tezacaftor/Ivacaftor Improved Clinical Outcomes in a Patient with N1303K-CFTR Based on Experimental Evidence. Am J Respir Crit Care Med. 2021; 204(10):1231-1235. PMC: 8759307. DOI: 10.1164/rccm.202101-0090LE. View

14.

Kolonko A, Efing J, Gonzalez-Espinosa Y, Bangel-Ruland N, Van Driessche W, Goycoolea F . Capsaicin-Loaded Chitosan Nanocapsules for wtCFTR-mRNA Delivery to a Cystic Fibrosis Cell Line. Biomedicines. 2020; 8(9). PMC: 7554911. DOI: 10.3390/biomedicines8090364. View

15.

Du M, Jones J, Lanier J, Keeling K, Lindsey J, Tousson A . Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med (Berl). 2002; 80(9):595-604. DOI: 10.1007/s00109-002-0363-1. View

16.

Ledford H, Callaway E . Pioneers of revolutionary CRISPR gene editing win chemistry Nobel. Nature. 2020; 586(7829):346-347. DOI: 10.1038/d41586-020-02765-9. View

17.

Ramalho A, Furstova E, Vonk A, Ferrante M, Verfaillie C, Dupont L . Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis. Eur Respir J. 2020; 57(1). DOI: 10.1183/13993003.02426-2019. View

18.

Quesada R, Dutzler R . Alternative chloride transport pathways as pharmacological targets for the treatment of cystic fibrosis. J Cyst Fibros. 2019; 19 Suppl 1:S37-S41. DOI: 10.1016/j.jcf.2019.10.020. View

19.

Howard M, Frizzell R, Bedwell D . Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996; 2(4):467-9. DOI: 10.1038/nm0496-467. View

20.

Murthy M, Pedemonte N, MacVinish L, Galietta L, Cuthbert A . 4-Chlorobenzo[F]isoquinoline (CBIQ), a novel activator of CFTR and DeltaF508 CFTR. Eur J Pharmacol. 2005; 516(2):118-24. DOI: 10.1016/j.ejphar.2005.04.037. View