Periodic Reporting for period 4 - RODRESET (Development of novel optogenetic approaches for improving vision in macular degeneration)
Okres sprawozdawczy: 2023-07-01 do 2024-12-31
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.
With respect to the strategy of direct manipulation of the rod cells, we have assessed and compared the ability of various single- and multi-gene transfer vectors to confer daylight sensation to rod photoreceptors. Having tested various optogenetic tools, with or without a complementary modulator of the endogenous phototransduction cascade, we have identified a vector that is able to restore electrical activity in the retina in response to wide range of higher light levels in animals that lack daylight vision. Further refinement and optimization of the vector are currently ongoing to ensure the best chance of success in a clinical trial. For the manipulation of the horizontal cells, we obtained evidence that the main premise of the approach is feasible. However, the improvement in retinal sensitivity that was achieved was not maintained, and the likely cause of this loss of benefit over time was identified. An optimised gene therapy vector is being produced, which we expect will allow a similar improvement in daylight vision to be maintained for the lifetime of the animals.
This project aims to develop gene therapy vectors to improve vision in patients who have lost central vision. The project uses two separate approaches that are different from the gene therapy treatments that have been developed thus far, and when successful, they could potentially improve the quality of life of a large number of people with sight impairments. The project has not fully achieved its aim within the planned timeframe, however the development and optimization of the vectors will continue. We anticipate that we will have at least one therapeutic vector that is ready for clinical trial in the near future.