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 C...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2014
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| _version_ | 1826306290763169792 |
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| author | Alton, E Boyd, A Cheng, S Davies, J Davies, L Dayan, A Gill, DR Griesenbach, U Higgins, T Hyde, S Innes, J McLachlan, G Porteous, D Pringle, I Scheule, R Sumner-Jones, S |
| author_facet | Alton, E Boyd, A Cheng, S Davies, J Davies, L Dayan, A Gill, DR Griesenbach, U Higgins, T Hyde, S Innes, J McLachlan, G Porteous, D Pringle, I Scheule, R Sumner-Jones, S |
| author_sort | Alton, E |
| collection | OXFORD |
| description | 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. © 2014 Macmillan Publishers Limited. |
| first_indexed | 2024-03-07T06:45:43Z |
| format | Journal article |
| id | oxford-uuid:fac7ed7e-379d-4ddc-8155-b635c227423d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:45:43Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:fac7ed7e-379d-4ddc-8155-b635c227423d2022-03-27T13:08:50ZToxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lungJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fac7ed7e-379d-4ddc-8155-b635c227423dEnglishSymplectic Elements at Oxford2014Alton, EBoyd, ACheng, SDavies, JDavies, LDayan, AGill, DRGriesenbach, UHiggins, THyde, SInnes, JMcLachlan, GPorteous, DPringle, IScheule, RSumner-Jones, SFor 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. © 2014 Macmillan Publishers Limited. |
| spellingShingle | Alton, E Boyd, A Cheng, S Davies, J Davies, L Dayan, A Gill, DR Griesenbach, U Higgins, T Hyde, S Innes, J McLachlan, G Porteous, D Pringle, I Scheule, R Sumner-Jones, S Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title | Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title_full | Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title_fullStr | Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title_full_unstemmed | Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title_short | Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung |
| title_sort | toxicology study assessing efficacy and safety of repeated administration of lipid dna complexes to mouse lung |
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