Cystic Fibrosis Gene Therapy in the UK and Elsewhere

Overview

Journal Hum Gene Ther

Specialties Genetics
Pharmacology

Date 2015 Apr 4

PMID 25838137

Citations 38

Authors

Uta Griesenbach

Kamila M Pytel

Eric W F W Alton

Affiliations

Soon will be listed here.

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.

Citing Articles

Highly branched poly β-amino ester/CpG-depleted plasmid nanoparticles for non-viral gene therapy in lung cystic fibrosis disease.

Qiu B, Manzanares D, Li Y, Wang X, Li Z, Terreau S Mol Ther Methods Clin Dev. 2025; 32(3):101292.

PMID: 40017666 PMC: 11866167. DOI: 10.1016/j.omtm.2024.101292.

AAV-based gene delivery of antimicrobial peptides to combat drug-resistant pathogens.

Baindara P, Roy D, Boosani C, Mandal S, Green J Appl Environ Microbiol. 2025; 91(2):e0170224.

PMID: 39760495 PMC: 11837516. DOI: 10.1128/aem.01702-24.

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.

The Road Less Traveled: Slow but Steady Progress Toward Cystic Fibrosis Gene Therapy by the UK Respiratory Gene Therapy Consortium.

Flotte T Am J Respir Crit Care Med. 2024; 210(12):1387-1389.

PMID: 39265185 PMC: 11716029. DOI: 10.1164/rccm.202408-1516ED.

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.

References

Moss R, Milla C, Colombo J, Accurso F, Zeitlin P, Clancy J . Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther. 2007; 18(8):726-32. DOI: 10.1089/hum.2007.022. View

Zabner J, Cheng S, Meeker D, Launspach J, Balfour R, Perricone M . Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J Clin Invest. 1997; 100(6):1529-37. PMC: 508334. DOI: 10.1172/JCI119676. View

Naehrlich L, Ballmann M, Davies J, Derichs N, Gonska T, Hjelte L . Nasal potential difference measurements in diagnosis of cystic fibrosis: an international survey. J Cyst Fibros. 2013; 13(1):24-8. DOI: 10.1016/j.jcf.2013.08.006. View

Yan Z, Keiser N, Song Y, Deng X, Cheng F, Qiu J . A novel chimeric adenoassociated virus 2/human bocavirus 1 parvovirus vector efficiently transduces human airway epithelia. Mol Ther. 2013; 21(12):2181-94. PMC: 3863803. DOI: 10.1038/mt.2013.92. View

Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M . Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989; 245(4922):1059-65. DOI: 10.1126/science.2772657. View

Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F . Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature. 2010; 467(7313):318-22. PMC: 3355472. DOI: 10.1038/nature09328. View

Bellon G, Michel-Calemard L, Thouvenot D, Jagneaux V, Poitevin F, Malcus C . Aerosol administration of a recombinant adenovirus expressing CFTR to cystic fibrosis patients: a phase I clinical trial. Hum Gene Ther. 1997; 8(1):15-25. DOI: 10.1089/hum.1997.8.1-15. View

Zhang L, Button B, Gabriel S, Burkett S, Yan Y, Skiadopoulos M . 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. PMC: 2705187. DOI: 10.1371/journal.pbio.1000155. View

Mietzsch M, Broecker F, Reinhardt A, Seeberger P, Heilbronn R . Differential adeno-associated virus serotype-specific interaction patterns with synthetic heparins and other glycans. J Virol. 2013; 88(5):2991-3003. PMC: 3958061. DOI: 10.1128/JVI.03371-13. View

10.

Palfi S, Gurruchaga J, Ralph G, Lepetit H, Lavisse S, Buttery P . Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014; 383(9923):1138-46. DOI: 10.1016/S0140-6736(13)61939-X. View

11.

Davies L, Nunez-Alonso G, McLachlan G, Hyde S, Gill D . Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy. Hum Gene Ther Clin Dev. 2014; 25(2):97-107. DOI: 10.1089/humc.2014.019. View

12.

Porteous D, Dorin J, McLACHLAN G, Davidson-Smith H, Davidson H, Stevenson B . Evidence for safety and efficacy of DOTAP cationic liposome mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 1997; 4(3):210-8. DOI: 10.1038/sj.gt.3300390. View

13.

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

14.

Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman N . Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 2012; 186(9):846-56. PMC: 3530223. DOI: 10.1164/rccm.201206-1056OC. View

15.

Penaud-Budloo M, Le Guiner C, Nowrouzi A, Toromanoff A, Cherel Y, Chenuaud P . Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J Virol. 2008; 82(16):7875-85. PMC: 2519600. DOI: 10.1128/JVI.00649-08. View

16.

Gill D, Southern K, Mofford K, Seddon T, Huang L, Sorgi F . A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 1997; 4(3):199-209. DOI: 10.1038/sj.gt.3300391. View

17.

Liu X, Luo M, Guo C, Yan Z, Wang Y, Lei-Butters D . Analysis of adeno-associated virus progenitor cell transduction in mouse lung. Mol Ther. 2008; 17(2):285-93. PMC: 2665184. DOI: 10.1038/mt.2008.248. View

18.

Russell W . Adenoviruses: update on structure and function. J Gen Virol. 2008; 90(Pt 1):1-20. DOI: 10.1099/vir.0.003087-0. View

19.

Potash A, Wallen T, Karp P, Ernst S, Moninger T, Gansemer N . Adenoviral gene transfer corrects the ion transport defect in the sinus epithelia of a porcine CF model. Mol Ther. 2013; 21(5):947-53. PMC: 3666638. DOI: 10.1038/mt.2013.49. View

20.

Boucher R . Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med. 2007; 58:157-70. DOI: 10.1146/annurev.med.58.071905.105316. View