Hypoxia-regulated transgene expression in experimental retinal and choroidal neovascularization.
Recombinant AAV vectors mediate efficient and sustained transgene expression in retinal tissues and offer a powerful approach to the local, sustained delivery of angiostatic proteins for the treatment of ocular neovascular disorders. The application of such strategies may also require regulated gene expression to minimize the potential for unwanted adverse effects. In this study, we have evaluated the effect of a hypoxia-responsive element (HRE) on the kinetics of recombinant adeno-associated (rAAV)-mediated reporter gene expression in murine models of retinal and choroidal neovascularization. In murine ischaemia-induced retinal neovascularization, intravitreal delivery of rAAV.HRE.GFP results in reporter gene expression specifically at sites of vascular closure during the period of active neovascularization and not after vector delivery in normal controls. In murine laser-induced choroidal neovascularization, subretinal delivery of rAAV.HRE.GFP results in reporter gene expression at sites of active neovascularization but not elsewhere or after vector delivery in normal controls. HRE-driven gene expression offers an attractive strategy for the targeted and regulated delivery of angiostatic proteins to the retina in the management of neovascular disorders.
Bainbridge
J W B
JW
Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Mistry
A
A
Binley
K
K
De Alwis
M
M
Thrasher
A J
AJ
Naylor
S
S
Ali
R R
RR
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D020256:Choroidal Neovascularization / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D005786:Gene Expression Regulation; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D000860:Hypoxia; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020218:Response Elements / Q000235:genetics; D015861:Retinal Neovascularization / Q000628:therapy*; D019076:Transgenes
D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins