Gene-dependent and -independent approaches for therapy of retinal diseases which are inaccessible to conventional gene therapy

Inherited retinal diseases (IRDs) are a major cause of blindness worldwide. Gene therapy represents an attractive therapeutic option for treatment of these diseases, and vectors based on adeno-associated viruses (AAVs) are considered the gold-standard for retinal cells transduction. As a confirmation of this, the first gene therapy product to receive a landmark market authorization in both the USA and Europe for treatment of a common form of IRD is based on an AAV vector. However, many tissue- and disease-related challenges in the field of retinal gene therapy are still unsolved, including the possibility to efficiently transfer large genes (>5 kb) via AAVs. Therefore, strategies to overcome such hurdles are being developed at a rapid pace. Our lab was set up in January 2021, we plan to focus our attention on developing AAV-based approaches which can tackle retinal diseases at multiple levels. We will explore novel gene replacement and genome editing approaches, which overcome the limitations of the existing ones, to directly provide a functional copy of diseased genes. In parallel, we will develop gene-independent gene therapy approaches to target key pathways which are altered in IRDs. We will use cutting-edge in vitro models, three-dimensional retinal organoids, and in vivo models. While our studies will be focused on testing these new approaches in common forms of IRDs due to mutations in large genes, such as Retinitis Pigmentosa and Stargardt disease, the overall goal of our project is to provide insights to treat additional common inherited and acquired retinal diseases. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from January 2022 until last budget year, calculated based on the size of the research group.