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Development of gene therapy strategies in rodent models of retinal degeneration.

Buch, P.; (2007) Development of gene therapy strategies in rodent models of retinal degeneration. Doctoral thesis , University of London. Green open access

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Abstract

Inherited retinal dystrophies constitute one of the most prevalent causes of bilateral visual loss, affecting as many as 1 in 3000 people. Genetic therapies have been developed following the identification of disease-causing mutations, using an understanding of how these mutations cause retinal degeneration and improved viral vectors designed to give safe and efficient gene delivery. Hence a broad range of retinal disorders may be treatable with gene therapy, although many aspects of ocular gene therapy warrant further investigation. The studies presented here aim to improve gene therapy in two well-characterised models of retinitis pigmentosa, the Prph2Rd2/Rd2 mouse and the RCS rat. Gene replacement therapy can be effective in these and other models, mediating both structural and functional improvement. However, in many cases long-term rescue from degeneration is not achieved, as evidenced by a continuing loss of photoreceptor cells. These studies aim to improve adeno-associated virus (AAV)-mediated gene delivery to the murine retina by using novel promoters to investigate the consequences of gene replacement therapy. Additionally an alternative viral vector (AAV2/5) will be used to enhance gene replacement, which gives faster and stronger transgene expression than the AAV2/2 used in previous studies. Cell death can also be prevented by administration of vectors expressing neurotrophic factors, but no study to date has identified such a factor that enhances gene replacement therapy indeed, AAV-mediated CNTF expression has serious deleterious effects on retinal function. Hence here we have investigated these deleterious effects, and determined whether CNTF can be used to prevent photoreceptor death without the reduction in retinal function seen previously. In addition, the ability of AAV-mediated GDNF expression to enhance gene replacement therapy in both the Prph2Kd2fRd2 mouse and the RCS rat has been evaluated in detail. These studies show for the first time that neurotrophic factor delivery, when used in combination with gene replacement therapy, can enhance structural and functional improvement in models of retinitis pigmentosa.

Type: Thesis (Doctoral)
Title: Development of gene therapy strategies in rodent models of retinal degeneration.
Identifier: PQ ETD:591864
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1444558
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