Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: neuroprotection • apoptosis/cell death • gene transfer/gene therapy