Research Project
10329081
Abstract To restore high quality, usable vision in patients, it is important to develop regenerative therapies in models that share key features of the human visual system, particularly a fovea, the retinal area specialized for high acuity vision. Pre-clinical testing has been challenging due to both the absence of models of foveal vision loss and the difficulty of demonstrating restored function. Under previous AGI funding, the Advanced Retinal Imaging Alliance at the University of Rochester has recently overcome these challenges to create a pre-clinical testing platform leveraging adaptive optics technology to: 1.) Create localized regions of photoreceptor ablation in the fovea that are axially confined, and 2.) Optically read out restored retinal ganglion cell function by performing cellular scale calcium imaging in the living eye. This system was developed to meet the needs of photoreceptor replacement therapy, which requires photoreceptor loss with preserved host retinal circuitry. Furthermore, a high-resolution in vivo imaging approach is well suited for pre-clinical evaluation of regenerative therapies where the timescales of restored connectivity are unknown and functional integration occurs on the cellular scale. In this proposal, we will use our platform to generate pre-clinical data that will inform future clinical trials of photoreceptor replacement therapy in patients. Functional integration of transplanted photoreceptors with the host retina requires both high-density delivery of high-quality donor photoreceptors and a host retina with the capacity for synaptogenesis. We have assembled a consortium that can explore and optimize both sides of this interaction. In continued collaboration with a team at the University of Wisconsin led by David Gamm, a clinician and expert in photoreceptor replacement therapy, we will evaluate survival and functional integration of transplanted photoreceptor precursors delivered to the sub-retinal space as aggregates or following incorporation into custom biodegradable scaffolds. In collaboration with a team at University of California, Berkeley led by Teresa Puthussery, an expert in retinal remodelling in retinal degeneration models and retinal histology, we will examine the impact of the loss of photoreceptor signalling on inner retina. We will explore whether deafferented cone bipolar cells can remodel and functionally integrate with donor photoreceptors and whether retinal hyperactivity develops in the fovea as it does in rodent. To make meaningful progress toward restoring vision in patients who have lived with vision loss for many years, we will examine how these phenomena develop in the fovea over time and whether the regenerative potential of the host can be improved by therapeutic interventions such as retinoic acid blockers. These studies will allow us to fully characterize our novel photoreceptor ablation model and deploy it with photoreceptor replacement therapies to advance the field toward clinical trials.
