Systemic adeno-associated virus-mediated gene therapy preserves retinal ganglion cells and visual function in DBA/2J glaucomatous mice.

A slow progressive death of neurons is the hallmark of neurodegenerative diseases, such as glaucoma. A therapeutic candidate, erythropoietin (EPO), has shown promise in many models of these diseases; however, it also causes polycythemia, a potentially lethal side effect. We have developed a novel mutant form of EPO that is neuroprotective but no longer erythropoietic by altering a single amino acid (arginine to glutamate at position 76; R76E). We hypothesized that a single intramuscular injection of recombinant adeno-associated virus carrying EpoR76E (rAAV2/5.CMV.EpoR76E) would protect retinal ganglion cells in a mouse model of glaucoma without inducing polycythemia. This systemic treatment not only protected the retinal ganglion cell somata located within the retina; it also preserved axonal projections within the optic nerve, while maintaining the hematocrit within normal limits. The rescued retinal ganglion cells retained their visual function demonstrated by flash visual evoked potentials. To our knowledge, this is the first demonstration of a therapy that protects neurons from death and prevents loss of visual function from the slow neurodegenerative effects of glaucoma. Because of its broad range of cellular targets, EpoR76E is likely to be successful in treating other neurodegenerative diseases as well.