The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep
| Autor: | J. Alastair Innes, Dominique McCormick, T Higgins, Heather E Davidson, Ronald K. Scheule, Deborah R. Gill, A. Christopher Boyd, Darren J. Shaw, Ian A. Pringle, Catherine Gordon, David J. Porteous, Eilidh Baker, Gerry McLachlan, Jane C. Davies, Rebecca Coles, S. C. Hyde, Eric W.F.W. Alton, Peter Tennant, David Collie, Uta Griesenbach, Alison Baker, Sionagh Smith, Michael McGovern, Stephanie G. Sumner-Jones, Seng H. Cheng, Christina Vrettou |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
medicine.medical_specialty Cystic Fibrosis Genetic enhancement Biophysics Bioengineering Pharmacology Bronchial brushing Cystic fibrosis Epithelium Biomaterials Internal medicine medicine Animals Adverse effect Gene transfer Lung Aerosols Hematology Sheep business.industry Gene Transfer Techniques Lipid medicine.disease Lipids medicine.anatomical_structure Mechanics of Materials Toxicity Immunology Ceramics and Composites Histopathology Female business |
| Zdroj: | Alton, E W, Baker, A, Baker, E, Boyd, C, Cheng, S H, Coles, R, Collie, D, Davidson, H, Davies, J C, Gill, D R, Gordon, C, Griesenbach, U, Higgins, T, Hyde, S C, Innes, J A, McCormick, D, McGovern, M, McLachlan, G, Porteous, D, Pringle, I A, Scheule, R K, Shaw, D, Smith, S, Summer-Jones, S, Tennant, P & Vrettou, C 2013, ' The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep ', Biomaterials, vol. 34, no. 38, pp. 10267-10277 . https://doi.org/10.1016/j.biomaterials.2013.09.023 |
| DOI: | 10.1016/j.biomaterials.2013.09.023 |
| Popis: | Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients. © 2013 Elsevier Ltd. |
| Databáze: | OpenAIRE |
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