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P. Colella, A. Auricchio; AAV-Mediated Gene Transfer of the Erythropoietin Derivative S100E in Models of Retinal Degenerative Diseases. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5357.
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We have previously reported that systemic adeno-associated viral (AAV) vector-mediated delivery of Erythropoietin (EPO) protects animal models of retinal diseases from photoreceptor degeneration. Translation of these findings into therapeutic application looks promising, however the erythrodifferentiating function of EPO represents a potential cause of several undesired side effects. Recently EPO derivatives that do not increase the hematocrit but retain tissue protective and anti-apoptotic functions have been identified. We are currently investigating the potential neuroprotective effects of the EPO mutant S100E (EpoS100E) in animal models of induced and inherited retinal degeneration to define the mechanisms of EPO neuroprotection in the retina and to find a mutation-independent treatment for RP and LCA aimed at slowing or halting photoreceptor degeneration.
We have constructed type I adeno-associated viral vectors (AAV1) expressing either wild type or EpoS100E. These vectors were used to transduce either muscle or retina of albino Lewis rats before inducing light-damage. EPO levels in rats fluids were measured by ELISA. Serum hematocrits were measured before and after AAV administration.
High EpoS100E levels were measured in the sera and ocular fluids of rats administered systemically and subretinally respectively. Interesting, systemic EpoS100E crosses the blood-retina barrier while intraocular EpoS100E does not leak to detectable levels in the circulation. None of the animal treated with EpoS100E had increased hematocrits. After light-damage we observed morphological photoreceptor protection in animals administered both systemically and intraocularly with AAV-CMV-EpoS100E.
Our data confirm that EpoS100E lacks hematopoietic activity and suggest that this EPO derivative retains neuroprotective effects in the retina. We are currently testing AAV-mediated EpoS100E delivery in genetic models of retinal degeneration.
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