The long-term goals of the work proposed in this grant application are to study neural plasticity of the adult mammalian visual system by adding new sensory input and to develop adeno virus associated vectors that efficiently transduce retinal cells when injected into the vitreous. Experiments that enhance rather than ablate sensory input offer a new avenue of research for answering fundamental questions about the plasticity of the adult visual system and have important implications for the rational design of gene therapy and retinal prostheses. Vectors that can deliver the therapeutic gene by injecting into the vitreous rather than into the subretinal space avoid the risk of damage to the retina from the injection procedure. We have chosen red- green color vision as a model system in which gain of function can be monitored quantitatively at the level of the retina using the electroretinogram and retinal electrophysiology and at the level of the visual cortex with behavioral tests of color vision, cortical physiology, and functional magnetic resonance imaging. Toward these goals we propose two specific aims:
Specific Aim 1. To determine how changes in the photopigments and cone subtypes in the retina affect the responses of retinal ganglion cells and neurons in the primary visual cortex. To determine how the neural responses of cells in treated adults differ from untreated dichromats and trichromats that were born with three cone types. To determine the mechanism the treated monkeys use to make trichromatic color discriminations and how they differ from naturally produced trichromats.
Specific aim 2. To determine whether the level of cone photoreceptor transduction achievable by intravitreal injection of new generation rAAV2 vectors carrying a human L opsin gene under control of the human L opsin promoter and enhancer is sufficient to change a protanopic (dichromatic) monkey's color vision to trichromatic.
Experiments that enhance rather than ablate sensory input, such as those described in this proposal, offer a new avenue of research for answering fundamental questions about the plasticity of the adult visual system and have important implications for the rational design of gene therapy and retinal prostheses. In addition, the experiments to develop less invasive methods for delivering the gene therapy vectors for retinal disease, will ultimately reduce the risks associated with treatment, making more retinal diseases accessible to this mode of therapy.
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