Online Issues

Journal Vol 50 (2)

Gene Therapy in Large Animal Models of Muscular Dystrophy

Zejing Wang, Jeffrey S. Chamberlain, Stephen J. Tapscott, and Rainer Storb

Zejing Wang, MD, PhD, is a research associate in the Program in Transplantation Biology of the Division of Clinical Research at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Jeffrey S. Chamberlain, PhD, is a professor in the Departments of Neurology, Biochemistry, and Medicine at the University of Washington in Seattle. Stephen J. Tapscott, MD, PhD, is a professor in the University of Washington Department of Medicine and a full member in the Division of Human Biology at the Fred Hutchinson Cancer Research Center. Rainer Storb, MD, is a full member in the Program in Transplantation Biology of the Division of Clinical Research at the Fred Hutchinson Cancer Research Center and a professor in the Department of Medicine at the University of Washington.

Address correspondence and reprint requests to Dr. Rainer Storb, Fred Hutchinson Cancer Research Center, Division of Clinical Research, 1100 Fairview Avenue N, D1-100, Seattle, WA 98109 or email rstorb@fhcrc.org.

Abstract

The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases characterized by progressive muscle wasting, which can lead to premature death in severe forms such as Duchenne muscular dystrophy (DMD). In many cases they are caused by the absence of proteins that are critical components of the dystrophin-glycoprotein complex, which links the cytoskeleton and the basal lamina. There is no effective treatment for these disorders at present, but several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. We review these strategies, which include the use of stem cells of different tissue origins, gene replacement therapies mediated by various viral vectors, and transcript repair treatments using exon skipping strategies. We comment on their advantages and on limitations that must be overcome before successful application to human patients. Our focus is on studies in a clinically relevant large canine model of DMD. Recent advances in the field suggest that effective therapies for muscular dystrophies are on the horizon. Because of the complex nature of these diseases, it may be necessary to combine multiple approaches to achieve a successful treatment.

Key Words: antisense oligonucleotide; dog model; dystrophin; gene therapy; immunosuppression; muscular dystrophy; stem cell; viral vector