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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016861-09
Application #
8617275
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Neuhold, Lisa
Project Start
2005-06-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
9
Fiscal Year
2014
Total Cost
$406,909
Indirect Cost
$174,159
Name
University of Washington
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Neitz, Maureen; Neitz, Jay (2014) Curing color blindness--mice and nonhuman primates. Cold Spring Harb Perspect Med 4:a017418
Schmidt, Brian P; Neitz, Maureen; Neitz, Jay (2014) Neurobiological hypothesis of color appearance and hue perception. J Opt Soc Am A Opt Image Sci Vis 31:A195-207
Bunce, John A; Isbell, Lynne A; Neitz, Maureen et al. (2011) Characterization of opsin gene alleles affecting color vision in a wild population of titi monkeys (Callicebus brunneus). Am J Primatol 73:189-96
Neitz, Jay; Neitz, Maureen (2011) The genetics of normal and defective color vision. Vision Res 51:633-51
Conway, Bevil R; Chatterjee, Soumya; Field, Greg D et al. (2010) Advances in color science: from retina to behavior. J Neurosci 30:14955-63
Mancuso, Katherine; Hauswirth, William W; Li, Qiuhong et al. (2009) Gene therapy for red-green colour blindness in adult primates. Nature 461:784-7
Mauck, Matthew C; Mancuso, Katherine; Kuchenbecker, James A et al. (2008) Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors. Vis Neurosci 25:273-82