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Gene therapy for ocular angiogenesis

Bainbridge, James William Braithwaite; (2003) Gene therapy for ocular angiogenesis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

This thesis describes a programme of work to develop local gene transfer of angiostatic proteins for the treatment of retinal and choroidal neovascular disorders. Current treatments are of limited efficacy and associated with significant adverse effects. Characterisation of the molecular and cellular events involved in angiogenesis has led to the identification of a number of angiostatic molecules with potential therapeutic value. The systemic administration of small molecule angiostatic proteins risks significant systemic adverse effects and if delivered intraocularly their half-life is short. Local gene transfer, however, offers the possibility of targeted, sustained and regulatable expression of angiostatic proteins to the retina after a single procedure to introduce a vector to an intraocular site. In order to investigate the potential value of this approach relevant animal models of retinal and choroidal angiogenesis were established and optimised. Viral vectors including adenoviral, adeno-associated viral and lentiviral vectors, expressing reporter genes and angiostatic proteins were produced. Reporter gene studies were performed to determine the kinetics of transgene expression following intraocular vector delivery in the models. Gene delivery of a vascular endothelial growth factor (VEGF) inhibitor, soluble Flt-1, significantly reduced neovascularisation in models of both retinal and choroidal angiogenesis, and had no apparent adverse effect in normal animals. Targeting of transgene expression to sites and periods of active neovascularisation was achieved by the incorporation of a hypoxia-responsive promoter into the gene construct. Pre-clinical studies of reporter gene transfer in a large animal model following subretinal delivery of a recombinant adeno-associated viral vector demonstrated efficient sustained reporter gene expression in cells of the outer retina. The findings of these studies were used to develop a proposal for a clinical phase I/II trial of gene therapy for choroidal neovascularisation in age-related macular degeneration by adeno-associated virus-mediated local expression of the VEGF inhibitor soluble sFlt-1.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Gene therapy for ocular angiogenesis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Gene therapy
URI: https://discovery.ucl.ac.uk/id/eprint/10100622
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