title: 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.
authors.affiliation: Telethon Institute of Genetics and Medicine, 80131 Naples, Italy.
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Colella
authors.forename: Carolina
authors.initials: C
authors.lastname: Iodice
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Vicino
authors.forename: Ida
authors.initials: I
authors.lastname: Annunziata
authors.forename: Enrico M
authors.initials: EM
authors.lastname: Surace
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000229:Dependovirus; D004920:Erythropoiesis; D004921:Erythropoietin / Q000235:genetics / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006400:Hematocrit; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008027:Light / Q000009:adverse effects*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064531:Peripherins; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D012162:Retinal Degeneration / Q000235:genetics / Q000628:therapy*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C498604:Aipl1 protein, mouse; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D064531:Peripherins; D004921:Erythropoietin