Usher syndrome (USH)

Usher syndrome (USH) is the most common cause of genetic deafblindness worldwide. While deafness can be treated with cochlear implants, there are currently no therapies for retinal defects. Mutations in the USH1B (MYO7A) gene encoding the myosin 7a protein are the main cause of the most severe Usher subtype. However, due to its size, this gene cannot be packaged into the gold standard adeno-associated viral (AAV) vectors for gene transfer. There is therefore an unmet medical need for the development and evaluation of novel strategies for the treatment of this disease. In the present project we aim to evaluate the i) gene replacement strategy of MYO7A ii) CRISPRa approach for activation of the MYO7B gene as a potential functional and/or structural counterpart of MYO7A. For gene transfer in both strategies, we will use the dual REVeRT AAV vector technology recently developed in our laboratory. The individual approaches will be evaluated in a mouse and pig model for USH1B and in human retinal organoids at the molecular, structural and functional level. Successful realization of these goals would pave the way for USH1B clinical trials.