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

Gene Therapy volume 21, pages 89–95 (2014)Cite this article

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Abstract

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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Acknowledgements

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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Author notes

  1. E W F W Alton, A C Boyd, J C Davies, D R Gill, U Griesenbach, T Higgins, S C Hyde, J A Innes and D Porteous: UK CF Gene Therapy Consortium Strategy Group and senior authors.

Authors and Affiliations

  1. UK CF Gene Therapy Consortium, London, Oxford and Edinburgh, UK,

    E W F W Alton, A C Boyd, J C Davies, L A Davies, D R Gill, U Griesenbach, T Higgins, S C Hyde, J A Innes, G McLachlan, D Porteous, I Pringle & S Sumner-Jones

  2. Department of Gene Therapy, Imperial College, London, UK

    E W F W Alton, J C Davies, U Griesenbach & T Higgins

  3. Medical Genetics Section, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    A C Boyd & D Porteous

  4. Genzyme, a Sanofi Company, Framingham, 01701, MA, USA

    S H Cheng & R K Scheule

  5. Gene Medicine Research Group, NDCLS, John Radcliffe Hospital, Oxford University, Oxford, UK

    L A Davies, D R Gill, S C Hyde, I Pringle & S Sumner-Jones

  6. Toxicology Consult, London, UK,

    A Dayan

  7. Scottish Adult Cystic Fibrosis Service, Western General Hospital, Edinburgh, UK

    J A Innes

  8. Roslin Institute, University of Edinburgh, Edinburgh, UK

    G McLachlan

Authors
  1. E W F W Alton
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  2. A C Boyd
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  3. S H Cheng
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  4. J C Davies
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  5. L A Davies
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  7. D R Gill
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  8. U Griesenbach
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  9. T Higgins
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  10. S C Hyde
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  11. J A Innes
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  12. G McLachlan
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  13. D Porteous
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  14. I Pringle
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  15. R K Scheule
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  16. S Sumner-Jones
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Corresponding authors

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

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Competing interests

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). https://doi.org/10.1038/gt.2013.61

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  • DOI: https://doi.org/10.1038/gt.2013.61

Keywords

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

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