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T. S. Rex, K. Kodali, T. A. Sullivan; Systemic Gene Delivery of a Modified Erythropoietin Protects the Photoreceptors in the Retinal Degeneration Slow Mouse. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5193.
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We previously showed protection of the photoreceptors after intramuscular delivery of a recombinant adeno-associated virus (rAAV) carrying erythropoietin (EPO). The goal of this study was to determine if a non-erythropoietic form of EPO can protect photoreceptor cells in the retinal degeneration slow mouse (rds/rds) without increasing hematocrit levels.
Using site-directed mutagenesis, we generated Epo-R103E. At postnatal day 7, rds/rds mice were given intramuscular injections of rAAV carrying eGFP, Epo, or Epo-R103E. At postnatal day 90, outer nuclear layer (ONL) thickness was examined by high-resolution optical coherence tomography and histological cross section. The ONL was measured every 0.5mm from the optic nerve head in all treatment groups. Hematocrit levels were determined by capillary centrifugation of blood and serum EPO levels were determined by ELISA. Real time quantitative PCR was performed on kidney samples to detect differences in endogenous EPO mRNA levels.
There was an average of three rows of nuclei in the ONL of rAAV.eGFP treated mice while the treatment groups contained at least six rows. Hematocrit levels in rAAV.eGFP, rAAV.Epo, and rAAV.Epo-R103E treated mice were 46%, 63%, and 52% respectively. Serum EPO levels for rAAV.eGFP, rAAV.Epo, and rAAV.Epo-R103E treated mice were 8, 117, and 332 mu/ml, respectively. No significant difference was detected in mouse EPO mRNA levels in treated vs. untreated groups.
Gene delivery of both forms of EPO protected the photoreceptors of rds/rds mice after an intramuscular injection. EPO-R103E provided protection of the photoreceptor cells without significantly increasing hematocrit levels, making it an attractive candidate for the treatment of inherited retinal degenerative diseases without the need for an intraocular injection.
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