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Pasqualina Colella, Carolina Iodice, Umberto Di Vicino, Ida Annunziata, Alberto Auricchio; Non-erythropoietic Erythropoietin Derivatives Preserve Photoreceptors From Light-induced And Genetic Degeneration: Insights Into Erythropoietin Neuroprotective Mechanism. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5461.
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Given inherited retinal degenerations (IRDs) high genetic heterogeneity, a wide-applicable treatment would be desirable to halt/slow the progressive photoreceptor (PR) cell loss in a mutation-independent manner. In addition to its erythropoietic activity Erythropoietin (EPO) is endowed with neurotrophic functions. We have previously shown that adeno-associated viral vector (AAV)-mediated systemic EPO delivery protects from PR degeneration. However this is associated with undesired hematocrit increase which could contribute to PR protection. Non-erythropoieitc EPO derivatives (EPO-D) are available which allow to dissect erythropoiesis role in PR preservation and may be more versatile and safe than EPO as anti-apoptotic agents.
We have delivered in animal models of light-induced or genetic retinal degeneration either intramuscularly or subretinally AAV vectors encoding EPO or one of three selected EPO-D: the mutant S100E, the helix B and the AB EPO-mimetic peptides.
We observed that systemic expression of S100E induces significant lower hematocrit increase than EPO while providing similar protection from PR degeneration. In addition, local intraocular expression of both EPO and EPO-D preserves PR from degeneration albeit at lower levels than when expressed sistemically, thus suggesting that the hormone systemic effects including erythropoiesis contribute but are not required for PR protection.
In conclusion, our data show that EPO protection from retinal PR degeneration, either induced or inherited, does not require hormone-induced erythropoiesis and can be exerted by non-erythropoietic EPO-D systemically or locally delivered to the retina by AAV. These may represent novel therapeutic agents for common conditions characterized by retinal degeneration.
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