Brain-Derived Neurotrophic Factor Gene Delivery to Müller Glia Preserves Structure and Function of Light-Damaged Photoreceptors

Abstract

To test the hypothesis that adenovirus (Ad)-mediated gene delivery of brain-derived neurotrophic factor (BDNF) to Müller cells can protect photoreceptors from light-induced retinal degeneration. Adult Sprague-Dawley rats received an intraocular injection of Ad.BDNF, control Ad containing the green fluorescent protein (GFP) gene, or BDNF recombinant protein. Animals were then exposed to 5, 10, or 16 days of constant light. The effect of Ad.BDNF on photoreceptor survival was examined histologically, by measuring the outer nuclear layer (ONL) thickness, and functionally, by measuring the electroretinographic (ERG) response. Ad.BDNF mediated sustained expression of bioactive neurotrophin by Müller cells that lasted for at least 30 days after viral vector administration. BDNF gene delivery to Müller glia markedly increased the survival and structural integrity of light-damaged photoreceptors. For example, after 10 days of exposure to light, the average percentage of ONL preservation in the superior central retina of eyes that received Ad.BDNF was 71%, compared with 46% in eyes that received a control Ad.GFP or 15% in contralateral eyes. Of importance, retinas exposed to Ad.BDNF had more photoreceptor nuclei than retinas that received a single intraocular injection of BDNF recombinant protein. The neuroprotective effect of Ad.BDNF was accompanied by preservation of the ERG response of the treated eyes. These data provide proof of the concept that BDNF gene transfer into Müller cells is an effective strategy for preserving structure and function of photoreceptors in retinal degeneration.