Journal
GENE THERAPY
Volume 21, Issue 1, Pages 89-95Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2013.61
Keywords
cystic fibrosis; gene transfer; cationic lipid; toxicology; repeat administration
Categories
Funding
- Cystic Fibrosis Trust
- NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust
- Imperial College London
- BBSRC [BBS/E/D/20221658] Funding Source: UKRI
- MRC [G0100266] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20221658] Funding Source: researchfish
- Medical Research Council [G0100266] Funding Source: researchfish
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For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-asociated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.
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