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Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung


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-associated 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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We thank Samia Soussi for help with preparing the manuscript. The work was funded by the Cystic Fibrosis Trust and supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

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Correspondence to A C Boyd, U Griesenbach or S C Hyde.

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SHC and RKS are employed by Genzyme/Sanofi and hold several patents related to cationic lipids. The remaining authors declare no conflict of interest.

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Alton, E., Boyd, A., Cheng, S. et al. Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung. Gene Ther 21, 89–95 (2014).

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  • cystic fibrosis
  • gene transfer
  • cationic lipid
  • toxicology
  • repeat administration

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