In vivo gene editing 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 (a) chains of the collagen VI monomer (COL6A1, COL6A2, and COL6A3). No disease-modifying therapies for these disorders currently exist. Here, we aim to test a single dose genetic therapy for treating collagen VI myopathies, using a pre-clinical mouse model that bears human-relevant Col6a2 mutations. Our strategy will utilize genome editing to correct the disease-causingmutation in skeletal muscle and muscle-resident stromal cells. This genome editing strategy is relevant for patients with either nonsense or missense point mutations (potentially up to ~57% of patients). Through this Developmentgrant, we will test the utility of our proposed strategy both for preventing the onset of disease and for rescuing already established disease, using Col6a2 mutant mice of different ages to represent different disease stages (pre-symptomatic, recent symptom onset, and severely symptomatic). Success in our studies will support future commercial development of this gene therapeutic approach to replace current costly and ineffective palliative care, which does not address the underlying cause of the disorder.