Can gene therapy expand sensory capacity in the adult?

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How plastic is the adult nervous system? Can an animal's behavior be changed by delivering a gene encoding a light sensitive protein to the appropriate neuron in the retina. If the answer to this question is yes, it means that the nervous systems is sufficiently plastic to allow remodeling of the adult neural circuitry to the extent that it would bring about a change in behavior. If the answer to this question is yes, it will have an enormous impact on our understanding of neural plasticity, it will open new vistas for gene therapy for human disease, and i will allow us to create a model system to directly probe the mechanisms by which neural circuits are established and remodeled. Most New World primates, including squirrel monkeys, have a single visual pigment gene on the X-chromosome. However, three alleles occur at this locus and each allele encodes a spectrally distinct pigment. The three alleles correspond to the L and M pigment genes that are the basis for red-green color vision in humans, and the monkeys have a single X- chromosome, and thus are a model for a form of inherited red-green color vision deficiency common among human males. This form of color vision loss in humans is caused by deletion of all but one of the visual pigment genes on the X chromosome. To have normal, trichromatic color vision, male humans must have at least one L and ne M pigment gene. Female squirrel monkeys who are heterozygous at the X-linked pigment gene locus have trichromatic color vision similar to that of humans. Thus, the neural circuitry necessary to establish trichromatic color vision is present in this species, and is clearly utilized when a third visual pigment gene is present during development. We propose to add, by subretinal injection of recombinant adeno-associated virus carrying a human L opsin gene, a third cone type to the adult male squirrel monkey retina. The three cone types will be the endogenous S and M cones of the male squirrel monkey retina, plus M clones transduced with the rAAV virus and expressing a human L pigment. We will monitor color vision behavior both before and after subretinal injection to determine whether the animal's color vision changes from dichromatic to trichromatic.