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Katherine Wert, Richard Davis, Javier Sancho-Pelluz, Chyuan-Sheng Lin, Stephen Tsang; Functional rescue for a full year after gene therapy in a pre-clinical model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4674.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations within the phosphodiesterase 6 (PDE6) complex are the third most common cause of autosomal recessive retinitis pigmentosa (RP). In a pre-clinical model of RP, the Pde6αD670G/Pde6αD670G mouse, there is a progressive loss of photoreceptor cells and neuronal function over time, due to a missense mutation in the alpha subunit of PDE6. No studies have been reported for any gene therapy for phototransduction defects that lasts beyond six months of age in the mouse. We hypothesized that a single treatment with a gene therapy vector to increase PDE6α levels would result in at least a full year of visual function in the pre-clinical model of RP (rescue for over half of the mouse lifespan and twice as long as previously reported studies).
An AAV2/8(Y733F) gene therapy vector driven by the cell-type specific rhodopsin promoter was utilized to deliver Pde6α: AAV2/8(Y733F)-Rho-Pde6α. A single subretinal injection of this gene therapy vector was delivered at post-natal day five in the pre-clinical model of RP, and results were analyzed between 7-12 months of age.
A single subretinal injection of the AAV2/8(Y733F)-Rho-Pde6α gene therapy virus was able to provide photoreceptor survival and visual function for over half of the mouse lifespan. As previously reported, the untreated Pde6αD670G/Pde6αD670G mutant mouse eyes lost all photoreceptor nuclei by five months of age and lost visual function by two months of age. However, histological analyses displayed photoreceptors present in the treated Pde6αD670G/Pde6αD670G mutant mouse eyes after seven months of age, and electroretinography confirmed these results with visual function present in the treated eyes for at least ten months of age.
Studies have shown that the efficacy of the AAV viral transduction is confined to the location of the subretinal bleb. However, a single subretinal injection of this therapeutic agent is able to provide long-term rescue for over half of the mouse lifespan. Our report provides evidence that this gene therapy agent will prevent disease progression in human patients with RP due to PDE6α deficiency.
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