Development of ALS gene therapies for targeted protein degradation of TDP-43

We have developed an AAV-based gene therapy which overexpresses a therapeutically-optimised cyclin F variant for the targeted clearance of cytoplasmic TDP-43 via the ubiquitin proteasome system (UPS). In parallel, we have developed a new approach for targeted clearance of TDP-43 via the autophagy pathway. This project will develop and evaluate a combinatorial therapeutic approach which combines both of these TDP-43 degraders within the same therapeutic gene cassette, to create a single therapeutic product.