Periodic Reporting for period 3 - RODRESET (Development of novel optogenetic approaches for improving vision in macular degeneration) Reporting period: 2022-01-01 to 2023-06-30 Summary of the context and overall objectives of the project In industrialized countries, age-related macular degeneration (AMD) is the leading cause of untreatable blindness. In addition to age-related disease, there are also inherited forms of macular degeneration, such as juvenile-onset Stargardt disease. These conditions, for which there are currently no effective treatments, involve the loss of photoreceptors in the central retina, where a high cone photoreceptor density is responsible for effecting high resolution vision. We recently discovered that cones can modulate the sensitivity of surrounding rod photoreceptors to enable them to be more effective in daylight conditions. In retinal disorders involving degeneration of the macular cones, this lateral interaction is impaired, leading to saturation of the rods’ dynamic range and impaired daylight vision. We have also discovered that direct modulation the neurons underlying this lateral interaction, the horizontal cells, improves quality of vision in mice lacking functional cones. Together, our results identify a specific circuitry underlying rod-mediated vision as a potential therapeutic target following macular degeneration. Here, we aim to exploit these new findings to re-establish the rods’ ability to function in daylight using two distinct approaches. Firstly, we will use direct modification of the rods to permanently shift their light sensitivity into the daylight range. A small area of modified rods that are effective in daylight, likely with a higher temporal resolution, would improve extra-foveal fixation and vision. Secondly, we intend to establish a system that confers light sensitivity onto horizontal cells, to replace light-mediated input from cones. This will restore the natural horizontal cell-derived modulation of light sensitivity to rods, allowing them to function in daylight. Thus, by utilizing our knowledge of specific aspects of retinal circuitry, we aim to develop novel therapies for improving vision in patients with advanced macular degeneration. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Various new gene therapy vectors have been created that aim to improve rod derived vision under daylight conditions in patients with macular degeneration. Functionality of these vectors has been tested and validated in the laboratory and the most potent are being taken forward. Testing of improvements in vision in animal models of retinal dystrophy is ongoing. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) By the end of the project, two new treatment approaches should be ready for translation into clinical trials. These trials will aim to test improvement of daylight vision in patients with focal photoreceptor loss after subretinal delivery of gene therapy vectors.
