Enhanced therapeutic potential of a microdystrophin with an extended C-terminal domain

Abstract

Gene replacement therapy is becoming a therapeutic option for patients with Duchenne muscular dystrophy. Truncated dystrophins that can be expressed from adeno-associated viral (AAV) vectors have been designed and shown to retain many, though not all, functional features of the full-length protein. These “microdystrophins” differ by their combination of hinges and spectrin-like repeats and the inclusion of functional domains. Several microdystrophins have advanced to the clinic, and although all have been shown to restore muscle force in preclinical models, they may differ in the efficiency of providing muscle resilience and resistance to contraction-induced stress. Here, we examine whether the inclusion of a highly evolutionarily conserved domain found at the C-Terminus of dystrophin may improve the therapeutic activity of microdystrophin. We find that adding this portion of the C-Terminal domain results in a microdystrophin that is maintained at higher levels in the transduced muscles, recruits the dystrophin-associated protein complex more effectively to the sarcolemma, provides improved histopathological benefit, and increases muscle force and resistance to damage in mice lacking dystrophin. These findings indicate that incorporation of the dystrophin C-Terminus is an enhancement for microdystrophin design and may improve functional benefit.