SERCA2a overexpression improves muscle function in a canine Duchenne muscular dystrophy model
Kasun Kodippili, Chady H. Hakim, Matthew J. Burke, Yongping Yue, James Teixeira, Keqing Zhang, Gang Yao, Gopal J. Babu, Roland W. Herzog, Dongsheng Duan
Abstract
vector genome particles of the AAV vector were injected into the extensor carpi ulnaris (ECU) muscles of four juvenile affected dogs. Contralateral ECU muscles received excipient. Three months later, we observed widespread transgene expression and significantly increased SERCA2a levels in the AAV-injected muscles. Treatment improved SR calcium uptake, significantly reduced calpain activity, significantly improved contractile kinetics, and significantly enhanced resistance to eccentric contraction-induced force loss. Nonetheless, muscle histology was not improved. To evaluate the safety of AAV SERCA2a therapy, we delivered the vector to the ECU muscle of adult normal dogs. We achieved strong transgene expression without altering muscle histology and function. Our results suggest that AAV SERCA2a therapy has the potential to improve muscle performance in a dystrophic large mammal.