The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep

被引：31

作者：

Alton, Eric W. F. W. ^{[1
]}

Baker, Alison ^{[2
,3
]}

Baker, Eilidh ^{[2
,3
]}

Boyd, A. Christopher ^{[4
]}

Cheng, Seng H. ^{[5
]}

Coles, Rebecca L. ^{[6
]}

Collie, D. David S. ^{[2
,3
]}

Davidson, Heather ^{[4
]}

Davies, Jane C. ^{[1
]}

Gill, Deborah R. ^{[6
]}

Gordon, Catherine ^{[2
,3
]}

Griesenbach, Uta ^{[1
]}

Higgins, Tracy ^{[1
]}

Hyde, Stephen C. ^{[6
]}

Innes, J. Alastair ^{[7
]}

McCormick, Dominique ^{[6
]}

McGovern, Michael ^{[4
]}

McLachlan, Gerry ^{[2
,3
]}

Porteous, David J. ^{[4
]}

Pringle, Ian ^{[6
]}

Scheule, Ronald K. ^{[5
]}

Shaw, Darren J. ^{[2
,3
]}

Smith, Sionagh ^{[2
,3
]}

Sumner-Jones, Stephanie G. ^{[6
]}

Tennant, Peter ^{[2
,3
]}

Vrettou, Christina ^{[2
,3
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Dept Gene Therapy, London SW3 6LR, England

[2] Univ Edinburgh, Roslin Inst, Roslin EH25 9RG, Midlothian, Scotland

[3] Univ Edinburgh, Royal Dick Sch Vet Studies, Roslin EH25 9RG, Midlothian, Scotland

[4] Univ Edinburgh, Inst Genet & Mol Med, Mol Med Ctr, Med Genet Sect, Roslin EH25 9RG, Midlothian, Scotland

[5] Genzyme Corp, Framingham, MA 01701 USA

[6] Univ Oxford, John Radcliffe Hosp, Nuffield Div Clin Lab Sci, Gene Med Res Grp,Radcliffe Dept Med, Oxford OX3 9DU, England

[7] Western Gen Hosp, Scottish Adult Cyst Fibrosis Serv, Edinburgh EH4 2XU, Midlothian, Scotland

来源：

BIOMATERIALS | 2013年 / 34卷 / 38期

基金：

英国生物技术与生命科学研究理事会;

关键词：

Gene transfer; Lipid; Lung; Epithelium; DOUBLE-BLIND; OVINE LUNG; EXPRESSION; AIRWAYS; DELIVERY; THERAPY; DISEASE;

D O I：

10.1016/j.biomaterials.2013.09.023

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

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. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：10267 / 10277

页数：11

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