Inherited retinal degenerations affect approximately 1 in 1,500 individuals in the US, and the prospect of treating these devastating diseases is a daunting task. While exciting progress has been made in the development of therapeutic strategies for these conditions in animal models, we currently lack sensitive tools to directly and immediately assess how various interventions might affect retinal health in human patients - clinical tools for assessing retinal structure and function are relatively insensitive and macroscopic. As such, there is a critical need to develop sensitive, noninvasive, cellular-resolution techniques for assessing photoreceptor structure and function. Adaptive optics imaging systems correct for the eye's optical aberrations, allowing imaging of individual rod and cone photoreceptor cells in the living human retina. Moreover, the same adaptive optics tools used to image the photoreceptor mosaic offer the potential to probe retinal function on a cellular scale, completely noninvasively. From a clinical perspective, these tools are in relative infancy, and we propose to help accelerate their translation through the following specific aims: 1) Define the therapeutic potential in human patients with achromatopsia, 2) Determine how L and M opsin mutations affect the integrity of the photoreceptor mosaic, and 3) Define the retinal phenotype in patients with retinitis pigmentosa and Usher syndrome, and determine how changes in the foveal cone mosaic affect visual function and sensitivity. The specific retinal degenerations were chosen because they represent a wide range of rod and cone involvement, are current or emerging targets for treatment efforts, and are a current strength of our collaborative team. This work is expected to have a significant positive impact, with the high-resolution genotype-phenotype relationships identified here providing a better understanding of the therapeutic potential in patients with inherited retinal degenerations as well as producing validated tools for assessing photoreceptor structure and function with cellular resolution. This proposal addresses 3 emerging needs identified in the NEI's Publication, "Vision Research: Needs, Gaps, and Opportunities": "Characterize the macula and perifoveal regions of the retina to better understand the predilection of the macula for disease," "Translate high- resolution retinal imaging technologies, like adaptive optics, into cost-effective and easy-to-use platforms for routine clinical use," and "Develop novel, noninvasive imaging techniques for monitoring electrical or metabolic activity of retinal neurons in vivo, ideally at the spatial resolution of photoreceptors or better for early detection of disease and monitoring of therapeutic intervention."
Current clinical tools for assessing retinal structure and function are relatively insensitive and may not be completely objective;as such, there is a need for sensitive, noninvasive, high-resolution techniques for assessing photoreceptor structure and function. This proposal employs advanced retinal imaging tools to investigate the cellular phenotype in a variety of inherited retinal diseases. These studies will accelerate the application of this imaging approach to define therapeutic potential on an individualized basis and to provide anatomical outcome measures for use in emerging therapeutic trials.
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