Non-erythropoietic erythropoietin derivatives protect from light-induced and genetic photoreceptor degeneration

Abstract

Given the high genetic heterogeneity of inherited retinal degenerations (IRDs), a wide applicable treatment would be desirable to halt/slow progressive photoreceptor (PR) cell loss in a mutation-independent manner. In addition to its erythropoietic activity, erythropoietin (EPO) presents neurotrophic characteristics. We have previously shown that adeno-associated viral (AAV) vector-mediated systemic EPO delivery protects from PR degeneration. However, this is associated with an undesired hematocrit increase that could contribute to PR protection. Non-erythropoietic EPO derivatives (EPO-D) are available which allow us to dissect erythropoiesis's role in PR preservation and may be more versatile and safe than EPO as anti-apoptotic agents. We delivered in animal models of light-induced or genetic retinal degeneration either intramuscularly or subretinally AAV vectors encoding EPO or one of the three selected EPO-D: the mutant S100E, the helix A- and B-derived EPO-mimetic peptides. We observed that (i) systemic expression of S100E induces a significantly lower hematocrit increase than EPO and provides similar protection from PR degeneration, and (ii) intraocular expression of EPO-D protects PR from degeneration in the absence of significant hematocrit increase. On the basis of this, we conclude that erythropoiesis is not required for EPO-mediated PR protection. However, the lower efficacy observed when EPO or S100E is expressed intraocularly rather than systemically suggests that hormone systemic effects contribute to PR protection. Unlike S100E, EPO-mimetic peptides preserve PR only when given locally, suggesting that different EPO-D have a different potency or mode of action. In conclusion, our data show that subretinal delivery of AAV vectors encoding EPO-D protects from light-induced and genetic PR degeneration.

Revisiting the role of erythropoietin for treatment of ocular disorders

“…Several distinguished investigations addressed the properties of the EPO to mediate protection against retinal damage through anti-apoptotic, 29,30 anti-oxidant, 22 and antiinflammatory 26,31 actions in hypoxia-, light-, and geneticinduced models. 5,8,12,15 Furthermore, Chung et al 20 reported on his finding for the expression of EPO and Figure 2 The role of erythropoietin in eye development via anti-apoptotic action. Binding of EPO/EPOR induces JAK2 phosphorylation, dimerization, and subsequently, activation of several tyrosine residues forming docking site for STAT, NF-κB, PI3-K/Akt, and MAPK.…”

“…Recent data indicates that there are expressions of heterodimer complex in the retina spread across the photoreceptor cells, INL and RGC. 15 More importantly, expression of βcR is also found on the eye stem cells. This has provided evidence that EPO can interact with heterodimer EPOR/ βcR complex, and that binding of the EPO to EPOR/βcR activates Wingless (Wnt) signaling pathway ( Figure 3).…”

“…Given the link between the protective response of EPO during eye development and the presence of EPOR in the retina, preliminary studies have looked into the potential role of EPO in the ocular system. Recent studies subjected to the use of EPO in various types of ocular disorders have reported on its neuroprotective functions such as antiapoptotic, 15,[19][20][21] anti-oxidant, [22][23][24][25] and anti-inflammatory properties. [26][27][28] However, their roles in the pathogenesis of ocular disorders were unclear.…”

“…EPO gene therapy using adeno-associated viral vector (AAV) for inherited retinal degeneration is an attractive mode of delivery. 15 Besides that, the retrobulbar injection of EPO for neuroprotection in glaucoma has been used in animal study and found to be effective. 78 From a practical aspect, retrobulbar procedure itself has many undesirable complications such as retrobulbar hemorrhage, globe perforation, and others.…”

“…They used non-erythropoietic EPO derivatives, which did not increase hematocrit level. 15 As EPO is a pleiotropic protein, there is a need to regulate expression from AAV vector. 95 Auricchio et al 96 showed that rapamacyin could control EPO expression from the vector in a dose-dependent manner and the expression was confined to the eye.…”