Non-Invasive Functional Assessments for Translational Retinal Therapeutics

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PROJECT SUMMARY As the first step in vision, photoreceptors have the crucial role of transducing light into a neural signal. Therefore, any dysfunction of photoreceptors through injury or disease is devastating to an individual’s vision. As a result, photoreceptors are the target of numerous clinical and preclinical therapies, all aimed at restoring their function. Unsurprisingly, preclinical and clinical trials place enormous value on outcome measures that can quickly reveal positive (or negative) functional effects as quickly as possible. Despite a veritable explosion of preclinical treatments, there is a relative dearth of cellular-scale non-invasive, in vivo functional assays for photoreceptors in the preclinical domain. Here, we propose to develop non-invasive in vivo functional tools and techniques to obtain and validate contrast-free functional signals from photoreceptors. This study aims to: 1) Characterize the intensity-based optoretinogram from photoreceptors in vivo using a tree shrew animal model, 2) Quantify and enhance the repeatability, reproducibility, and throughput of functional imaging in the tree shrew, and 3) Validate the optoretinogram against “gold standard” measurements of photoreceptor function in the tree shrew retina using mechanically and pharmacologically induced retinal degenerations. We will address these goals by use of an animal-compatible adaptive optics scanning laser ophthalmoscope, and the northern tree shrew animal model (Tupaia belangeri). We will first reverse-translate the previously developed intensity-based optoretinogram from humans to the tree shrew. Next, we will establish the minimum meaningful change that can be observed using an iORG in the tree shrew, assess inter-session reproducibility, and develop tools to enhance efficient imaging in small animal models. Finally, we will utilize the flexibility of the tree shrew animal model to investigate the ability of our nascent assays to sensitively measure functional change in pharmacologically and mechanically induced retinal degenerations. The expected outcomes of this work are to have established a valuable functional imaging technique in the tree shrew that is capable of assessing functional change at the level of an individual cell, and to develop imaging tools that are applicable to small animal imaging beyond the tree shrew. Ultimately, we expect these outcomes to facilitate the translation of novel preclinical therapies to humans.