Development of novel AAV-mediated in vivo gene editing approaches to treat inherited collagen VI-related myopathies

Collagen VI-related myopathies comprise a range of mild to severe inherited muscle diseases that are caused by mutations in the genes encoding the alpha chains of the collagen VI monomer. No disease-modifying therapies for these degenerative disorders currently exist. In this proposal, we present two novel therapeutic approaches for collagen VI myopathies based on adeno- associated virus (AAV) mediated in vivo gene editing. Specifically, we will test 1) an engineered adenine base editor to correct Col6a2 nonsense mutations and 2) a Cas7-11 nuclease to reduce the expression of pathogenic variants of Col6a3. We will then advance the more promising strategy to initial in vivo testing in the relevant pre-clinical mouse model. Results from our studies will provide essential proof-of-concept and pre-clinical testing of these targeted genome editing approaches for collagen VI myopathies. This work will be foundational for future development of a single-dose human gene therapy that has the potential to replace the current costly standard-of-care supports, which provide only limited palliative effect and fail to address the underlying cause of these disorders.