AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.7691
Submit to GPD
Cite this article
8
Download
114
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
REVIEW ARTICLE

Gene therapy for the treatment of cystic fibrosis: A brief review

Sandipan Nag1 ,  Soumili Ghosh1 ,  Surupa Basu2 ,  Apurba Ghosh2 ,  Pranab Roy2*
Show Less
1 Department of Biotechnology, Haldia Institute of Technology, Haldia, West Bengal, India
2 Department of Molecular Biology, Institute of Child Health, Kolkata, West Bengal, India
GPD, 7691 https://doi.org/10.36922/gpd.7691
Submitted: 16 December 2024 | Revised: 22 January 2025 | Accepted: 6 February 2025 | Published: 3 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

Cystic fibrosis (CF) is a life-threatening autosomal recessive disorder resulting from mutations in the CF transmembrane conductance regulator (CFTR) gene, impacting epithelial cells of the respiratory, gastrointestinal, and reproductive systems. Although the disease has been known for a long time, there is still no effective and well-established treatment for the condition. Lung ailments, caused by pulmonary tract obstruction and secondary infections, are the major cause of morbidity and mortality in CF patients. Since the cloning of the CFTR gene in 1989, there has been significant interest in developing gene therapies for CF, with a focus on treating lung disease. Over the decades, significant advances have been made in the development of vectors for the efficient delivery of the functional CFTR gene to the pulmonary tract and in designing better pharmacologic CFTR modulators to correct malfunctioning CFTR protein. This review aims to summarize some significant breakthroughs in the development of gene therapies for CF, the challenges encountered at every stage, the lessons learned from past trials, and measures taken to address them in recent advancements, including the role of emerging technologies such as clustered regularly interspaced short palindromic repeats/Cas9 gene editing. Moreover, this review briefly discusses other promising developments in CF treatment, such as alternative therapeutic strategies, safer and more effective delivery vectors, emerging gene editing methodologies, and the development of improved animal models.

Graphical abstract
Keywords
Cystic fibrosis
Cystic fibrosis transmembrane conductance regulator
Gene therapies
Gene editing
Animal models
Funding
None.
Conflict of interest
The authors declare that they have no competing interest.
References
  1. Guo J, Garratt A, Hill A. Worldwide rates of diagnosis and effective treatment for cystic fibrosis. J Cyst Fibros. 2022;21(3):456-462. doi: 10.1016/j.jcf.2022.01.009

 

  1. Yan Z, McCray PB Jr., Engelhardt JF. Advances in gene therapy for cystic fibrosis lung disease. Hum Mol Genet. 2019;28(R1):R88-R94. doi: 10.1093/hmg/ddz139

 

  1. Sui H, Xu X, Su Y, et al. Gene therapy for cystic fibrosis: Challenges and prospects. Front Pharmacol. 2022;13:1015926. doi: 10.3389/fphar.2022.1015926

 

  1. Purushothaman AK, Natarajan S, Panigrahi T, Nelson EJ. Diagnosis and treatment of cystic fibrosis in India: What is at stake for developing countries? J Biosci. 2024;49(3):64. doi: 10.1007/s12038-024-00456-5

 

  1. O’Connor GT, Quinton HB, Kneeland T, et al. Median household income and mortality rate in cystic fibrosis. Pediatrics. 2003;111(4 Pt 1):e333-e339. doi: 10.1542/peds.111.4.e333

 

  1. McGarry ME, Williams WA 2nd, McColley SA. The demographics of adverse outcomes in cystic fibrosis. Pediatr Pulmonol. 2019;54(Suppl 3):S74-S83. doi: 10.1002/ppul.24434

 

  1. Petrova N, Balinova N, Marakhonov A, et al. Ethnic differences in the frequency of CFTR gene mutations in populations of the European and North Caucasian part of the Russian Federation. Front Genet. 2021;12:678374. doi: 10.3389/fgene.2021.678374

 

  1. Alton EW, Boyd AC, Davies JC, et al. Genetic medicines for CF: Hype versus reality. Pediatr Pulmonol. 2016;51(S44):S5-S17. doi: 10.1002/ppul.23543

 

  1. Ooi CY, Durie PR. Cystic fibrosis from the gastroenterologist’s perspective. Nat Rev Gastroenterol Hepatol. 2016;13(3):175-185. doi: 10.1038/nrgastro.2015.226

 

  1. Gelfond D, Ma C, Semler J, Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 2013;58(8):2275-2281. doi: 10.1007/s10620-012-2209-1

 

  1. Castaldo A, Gelzo M, Iacotucci P, et al. One year of treatment with elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis homozygous for the F508del mutation causes a significant increase in liver biochemical indexes. Front Mol Biosci. 2024;10:1327958. doi: 10.3389/fmolb.2023.1327958

 

  1. Armstrong DK, Cunningham S, Davies JC, Alton EWF. Gene therapy in cystic fibrosis. Arch Dis Child. 2014;99(5):465-468. doi: 10.1136/archdischild-2012-302158

 

  1. Lee JA, Cho A, Huang EN, et al. Gene therapy for cystic fibrosis: New tools for precision medicine. J Transl Med. 2021;19:452. doi: 10.1186/s12967-021-03099-4

 

  1. Johnson LG, Olsen JC, Sarkadi B, Moore KL, Swanstrom R, Boucher RC. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nat Genet. 1992;2(1):21-25. doi: 10.1038/ng0992-21

 

  1. Zhang L, Button B, Gabriel SE, et al. CFTR delivery to 25% of surface epithelial cells restores normal rates of mucus transport to human cystic fibrosis airway epithelium. PLoS Biol. 2009;7(7):e1000155.

 

  1. Yan Z, McCray PB Jr., Engelhardt JF. Advances in gene therapy for cystic fibrosis lung disease. J Clin Invest. 2021;131(1):e123456. doi: 10.1172/JCI123456

 

  1. Zabner J, Petersen DM, Puga AP, et al. Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats. Nat Genet. 1994;6(1):75-83.

 

  1. Yei S, Mittereder N, Tang K, O’Sullivan C, Trapnell BC. Adenovirus-mediated gene transfer for cystic fibrosis: Quantitative evaluation of repeated in vivo vector administration to the lung. Gene Ther. 1994;1(3):192-200.

 

  1. Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther. 2020;28(3):709-722.

 

  1. Flotte TR, Ng P, Dylla DE, et al. Viral vector-mediated and cell-based therapies for treatment of cystic fibrosis. Mol Ther. 2007;15(2):229-241.

 

  1. Simon RH, Engelhardt JF, Yang Y, et al. Adenovirus-mediated transfer of the CFTR gene to lung of nonhuman primates: Toxicity study. Hum Gene Ther. 1993;4(6):771-780.

 

  1. O’Neal WK, Zhou H, Morral N, et al. Toxicity associated with repeated administration of first-generation adenovirus vectors does not occur with a helper-dependent vector. Mol Med. 2000;6(3):179-195.

 

  1. Parks RJ, Chen L, Anton M, Sankar U, Rudnicki MA, Graham FL. A helper-dependent adenovirus vector system: removal of helper virus by Cre-mediated excision of the viral packaging signal. Proc Natl Acad Sci USA. 1996;93(24):13565-13570.

 

  1. Toietta G, Koehler DR, Finegold MJ, Lee B, Hu J, Beaudet AL. Reduced inflammation and improved airway expression using helper-dependent adenoviral vectors with a K18 promoter. Mol Ther. 2003;7(5 Pt 1):649-658.

 

  1. Cao H, Yang T, Li XF, et al. Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression. Gene Ther. 2011;18(2):173-181.

 

  1. Cao H, Ouyang H, Grasemann H, et al. Transducing airway basal cells with a helper-dependent adenoviral vector for lung gene therapy. Hum Gene Ther. 2018;29(6):643-652.

 

  1. Koehler DR, Frndova H, Leung K, et al. Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter. J Gene Med. 2005;7(11):1409-1420.

 

  1. Hallek M, Wendtner CM. Recombinant adeno-associated virus (rAAV) vectors for somatic gene therapy: Recent advances and potential clinical applications. Cytokines Mol Ther. 1996;2(2):69-79.

 

  1. Wagner JA, Reynolds T, Moran ML, et al. Efficient and persistent gene transfer of AAV-CFTR in maxillary sinus. Lancet. 1998;351(9117):1702-1703. doi: 10.1016/S0140-6736(05)77740-0

 

  1. Moss RB, Milla C, Colombo J, et al. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A randomized placebo-controlled phase 2B trial. Hum Gene Ther. 2007;18(8):726-732. doi: 10.1089/hum.2007.022

 

  1. Moss RB, Rodman D, Spencer LT, et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: A multicenter, double-blind, placebo-controlled trial. Chest. 2004;125(2):509-521. doi: 10.1378/chest.125.2.509

 

  1. Lomunova MA, Gershovich PM. Gene therapy for cystic fibrosis: Recent advances and future prospects. Acta Nat. 2023;15(2):20. doi: 10.32607/actanaturae.11708

 

  1. Steines B, Dickey DD, Bergen J, et al. CFTR gene transfer with AAV improves early cystic fibrosis pig phenotypes. JCI Insight. 2016;1(14):e88728. doi: 10.1172/jci.insight.88728

 

  1. McClain LE, Davey MG, Zoltick PW, Limberis MP, Flake AW, Peranteau WH. Vector serotype screening for use in ovine perinatal lung gene therapy. J Pediatr Surg. 2016;51(5):879-884. doi: 10.1016/j.jpedsurg.2016.02.048

 

  1. Vidovic D, Carlon MS, da Cunha MF, et al. rAAV-CFTRΔR rescues the cystic fibrosis phenotype in human intestinal organoids and cystic fibrosis mice. Am J Respir Crit Care Med. 2016;193(3):288-298. doi: 10.1164/rccm.201505-0914OC

 

  1. Yan Z, Sun X, Feng Z, et al. Transcriptional silencing of CFTR gene expression in well-differentiated human airway epithelia. Hum Gene Ther. 2015;26:334-346. doi: 10.1089/hum.2015.001

 

  1. Ostedgaard LS, Rokhlina T, Karp PH, et al. A functional CFTR construct restores cAMP-stimulated anion transport after genomic integration in CF airway epithelia. Proc Natl Acad Sci U S A. 2005;102:2952-2957. doi: 10.1073/pnas.0409845102

 

  1. Marquez Loza LI, Yuen EC. Lentiviral vectors for the treatment and prevention of cystic fibrosis lung disease. Genes (Basel). 2019;10(3):218. doi: 10.3390/genes10030218

 

  1. Cooney AL, Abou Alaiwa MH, Shah VS, et al. Lentiviral-mediated phenotypic correction of cystic fibrosis pigs. JCI Insight. 2016;1(14):e88730. doi: 10.1172/jci.insight.88730

 

  1. Mitomo K, Griesenbach U, Inoue M, et al. Toward gene therapy for cystic fibrosis using a lentivirus pseudotyped with Sendai virus envelopes. Mol Ther. 2010;18:1173-1182.

 

  1. Griesenbach U, Inoue M, Meng C, et al. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 2012;186:846-856. doi: 10.1164/rccm.201206-1056OC

 

  1. Alton WF, Beekman JM, Boyd AC, et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax. 2016;72(2):137. doi: 10.1136/thoraxjnl-2016-208406

 

  1. Zabner J, Fasbender AJ, Moninger T, et al. Cellular and molecular barriers to gene transfer by a cationic lipid. J Biol Chem. 1995;270(32):18997-19007. doi: 10.1074/jbc.270.32.18997

 

  1. Caplen NJ, Alton EW, Middleton PG, et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med. 1995;1(1):39-46. doi: 10.1038/nm0195-39

 

  1. Alton WF, Boyd AC, Porteous DJ, et al. A phase I/IIa safety and efficacy study of nebulized liposome-mediated gene therapy for cystic fibrosis supports a multidose trial. Am J Respir Crit Care Med. 2015;192(11):1389. doi: 10.1164/rccm.201506-1193LE

 

  1. Alton WF, Armstrong DK, Ashby D, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: A randomized, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):684. doi: 10.1016/S2213-2600(15)00245-3

 

  1. Robinson E, MacDonald KD, Slaughter K, et al. Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Mol Ther. 2018;26(8):2034. doi: 10.1016/j.ymthe.2018.05.014

 

  1. Robinson E, MacDonald KD, Slaughter K, et al. Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis. Mol Ther. 2018;26(8):2034. doi: 10.1016/j.ymthe.2018.05.014

 

  1. Mastorakos P, Chisholm J, Song E, et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A. 2015;112(28):8720. doi: 10.1073/pnas.1502281112

 

  1. Quijano E, Bahal R, Ricciardi A, Saltzman WM, Glazer PM. Therapeutic peptide nucleic acids: Principles, limitations, and opportunities. Yale J Biol Med. 2017;90(4):583.

 

  1. McNeer NA, Anandalingam K, Fields RJ, et al. Correction of F508del CFTR in airway epithelium using nanoparticles delivering triplex-forming PNAs. Nat Commun. 2015;6:6952. doi: 10.1038/ncomms7952

 

  1. Papaioannou I, Simons JP, Owen JS. Oligonucleotide-directed gene-editing technology: Mechanisms and future prospects. Expert Opin Biol Ther. 2012;12(3):329-342. doi: 10.1517/14712598.2012.660522

 

  1. Beumer W, Swildens J, Henig N, et al. WS01.2 QR-010, an RNA therapy, restores CFTR function using in vitro and in vivo models of ΔF508 CFTR. J Cyst Fibros. 2015;14:S1.

 

  1. Matecki S, Kent L, de Boeck K, et al. Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis? J Cyst Fibros. 2016;15(1):10-20. doi: 10.1016/j.jcf.2015.03.015

 

  1. Beumer W, Swildens J, Leal T, et al. Evaluation of eluforsen, a novel RNA oligonucleotide for restoration of CFTR function in in vitro and murine models of p.Phe508del cystic fibrosis. PLoS One. 2019;14(6):e0219182. doi: 10.1371/journal.pone.0219182

 

  1. Sermet-Gaudelus I, Clancy JP, Nichols DP, et al. Antisense oligonucleotide eluforsen improves CFTR function in F508del cystic fibrosis. J Cyst Fibros. 2018;18(4):536. doi: 10.1016/j.jcf.2018.10.015

 

  1. Marangi M, Pistritto G. Innovative therapeutic strategies for cystic fibrosis: Moving forward to CRISPR technique. Front Pharmacol. 2018;9:396. doi: 10.3389/fphar.2018.00396

 

  1. Graham C, Hart S. CRISPR/Cas9 gene editing therapies for cystic fibrosis. Expert Opin Biol Ther. 2021;21:767-780. doi: 10.1080/14712598.2021.1869208

 

  1. Hirakawa MP, Krishnakumar R, Timlin JA, Carney JP, Butler KS. Gene editing and CRISPR in the clinic: Current and future perspectives. Biosci Rep. 2020;40(4):BSR20200127. doi: 10.1042/bsr20200127

 

  1. Lees-Miller SP, Meek K. Repair of DNA double-strand breaks by non-homologous end joining. Biochimie. 2003;85(11):1161-1173. doi: 10.1016/j.biochi.2003.10.011

 

  1. Brandsma I, Gent DC. Pathway choice in DNA double strand break repair: Observations of a balancing act. Genome Integr. 2012;3(1):9. doi: 10.1186/2041-9414-3-9

 

  1. Manjunath M, Choudhary B, Raghavan SC. SCR7, a potent cancer therapeutic agent and a biochemical inhibitor of nonhomologous DNA end‐joining. Cancer Rep. 2021;4(3):e1341. doi: 10.1002/cnr2.1341

 

  1. Singh P, Schimenti JC, Bolcun-Filas E. A mouse geneticist’s practical guide to CRISPR applications. Genetics. 2015;199(1):1-15. doi: 10.1534/genetics.114.169771

 

  1. Chen Y, Liu X, Zhang Y, et al. A self-restricted CRISPR system to reduce off-target effects. Mol Ther. 2016;24(9):1508-1510. doi: 10.1038/mt.2016.172

 

  1. Cromwell CR, Sung K, Park J, et al. Incorporation of bridged nucleic acids into CRISPR RNAs improves Cas9 endonuclease specificity. Nat Commun. 2018;9(1):1448. doi: 10.1038/s41467-018-03927-0

 

  1. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464-471. doi: 10.1038/nature24644

 

  1. Grünewald J, Zhou R, Lareau CA, et al. A dual-deaminase CRISPR base editor enables concurrent adenine and cytosine editing. Nat Biotechnol. 2020;38(7):861-864. doi: 10.1038/s41587-020-0535-y

 

  1. Jeong YK, Song B, Bae S. Current status and challenges of DNA base editing tools. Mol Ther. 2020;28(9):1938-1952. doi: 10.1016/j.ymthe.2020.07.021

 

  1. Rosen BH, Chanson M, Gawenis LR, et al. Animal and model systems for studying cystic fibrosis. J Cyst Fibros. 2018;17(2S):S28-S34. doi: 10.1016/j.jcf.2017.09.001

 

  1. Guilbault C, Saeed Z, Downey GP, Radzioch D. Cystic fibrosis mouse models. Am J Respir Cell Mol Biol. 2007;36(1):1-7. doi: 10.1165/rcmb.2006-0184TR

 

  1. Yan Z, Stewart ZA, Sinn PL, et al. Ferret and pig models of cystic fibrosis: prospects and promise for gene therapy. Hum Gene Ther Clin Dev. 2014;150127063140004. doi: 10.1089/hum.2014.154

 

  1. Sun X, Yi Y, Yan Z, et al. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Sci Transl Med. 2019;11(485):eaau7531. doi: 10.1126/scitranslmed.aau7531

 

  1. Demchenko A, Belova L, Balyasin M, et al. Airway basal cells from human-induced pluripotent stem cells: A new frontier in cystic fibrosis research. Front Cell Dev Biol. 2024;12:1336392. doi: 10.3389/fcell.2024.1336392

 

  1. Okuda K, Dang H, Kobayashi Y, et al. Secretory cells dominate airway CFTR expression and function in human airway superficial epithelia. Am J Respir Crit Care Med. 2021;203(10):1275-1289. doi: 10.1164/rccm.202008-3198OC

 

  1. Dean CH, Snelgrove RJ. New rules for club development: new insights into human small airway epithelial club cell ontogeny and function. Am J Respir Crit Care Med. 2018;198(11):1355-1356. doi: 10.1164/rccm.201805-0925ED

 

  1. Corti M, Cleaver B, Clément N, et al. Evaluation of readministration of a recombinant adeno-associated virus vector expressing acid alpha-glucosidase in Pompe disease: Preclinical to clinical planning. Hum Gene Ther Clin Dev. 2015;26(3):185-193. doi: 10.1089/humc.2015.068

 

Next article in this issue
Share
Back to top
Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept