"In this project the applicant proposes to develop a treatment strategy for a devastating blinding disorder affecting photoreceptor function within the first decade of life, X-linked Retinitis pigmentosa (XLRP). No treatment option exists to date.The proposed treatment strategy is based on the idea of inducing homology directed repair (HDR) of the mutation by promoting the exchange between the endogenous mutated chromosomal sequence and an exogenous repair DNA template at a double strand break (DSB) site in vivo. The treatment will be realized by co-delivery of endonucleases and the template DNA via adeno-associated virus (AAV) based gene transfer. However, This strategy has never been applied in the retina in vivo and therefore, several parameters are unknown, i.e. the average frequency of HDR in photoreceptors, whether DNA repair will take place through HDR or not, and the average length of the DNA conversion tract during HDR.The project includes the following parts: 1. Establishing the HDR frequency in photoreceptors in vivo: it is planned to optimize the frequency by co-delivery of trophic factors for the stimulation of the cellular repair machinery. 2. Inducing a bias of repair events towards HDR: it is planned to use nickases that only cut one DNA strand or will edit the expression profile of sensor proteins in the repair pathway in vitro and in vivo. 3. Optimization of the DNA conversion tract length: the expression profiles of helicases and other repair proteins are edited in vitro and in vivo. 4. Treatment of the PRGR2793delA mouse model: The optimized treatment settings are identified in order to test them for functional and morphological rescue effects.Results from this study will significantly advance the state of the art in targeted gene correction strategies in vivo and patients with XLRP and other hereditary disorders will potentially benefit from it through extrapolating the results for a broader application."