Potential Synergistic Protection of Retinal Ganglion Cells from Axotomy-Induced Apoptosis by Adenoviral Administration of Glial Cell Line-Derived Neurotrophic Factor and X-Chromosome-Linked Inhibitor of Apoptosis

Abstract

Following transection of the optic nerve (ON) in the adult rat, retinal ganglion cells (RGCs) undergo degeneration, and within 14 days 85% of axotomized RGCs die by apoptosis. Adenoviral delivery of the mammalian caspase inhibitor X-chromosome-linked inhibitor of apoptosis (Ad.XIAP) to the ON stump leads to expression exclusively in RGCs and rescues 18.9% of the RGCs that would degenerate without treatment. Following adenoviral vector injection into the vitreous body, bioactive glial cell line-derived neurotrophic factor (Ad.GDNF) is expressed in the retina and secreted to rescue 22.8% of lesioned RGCs. Here we report that coadministration of Ad.XIAP retrogradely directed to RGCs and intravitreal Ad.GDNF acts synergistically to protect axotomized RGCs. Combination treatment rescued 47.3% of RGCs that would undergo apoptosis without any treatment as opposed to 37.4% that would be expected if the two treatments acted independently. While without treatment only 15% of axotomized RGCs would survive, combination treatment resulted in survival of 55.4% of the total RGC population. These findings underline the neuroprotective potential of synergistic effects of a combination of different treatment strategies.