Gene Therapy in Large Animal Models of Muscular Dystrophy

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.

Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

“…A rationale for the other muscle groups not demonstrating a significantly lower T 2 is difficult to reconcile, but may be due, in part, to the variability of T 2 values among the canines, the relatively small changes observed, and the small sample size. We performed this investigation in the GRMD model because it is the largest available animal model of DMD and is considered the gold standard for evaluation of novel therapeutic interventions for DMD (Wang et al, 2009). The phenotype of the GRMD model most closely resembles the human disease with progressive muscle wasting, degeneration and fibrosis, and shortened life span secondary to respiratory failure or cardiomyopathy (Wang et al, 2009).…”

“…Thousands of mutations in the 79-exon dystrophin gene have been reported, with the most severe cases being associated with disruption of the reading frame and loss of functional dystrophin production (Aartsma-Rus et al, 2006). Boys typically present with symptoms of muscle weakness by age five, become wheelchair-bound by early to mid teens, and die from respiratory failure or cardiomyopathy in their late teens to early twenties (Muntoni et al, 2003;Tyler, 2003;Wang et al, 2009). Patients with dystrophin mutations that maintain the reading frame and produce truncated but partially functional dystrophin exhibit the milder phenotype of Becker muscular dystrophy (Aartsma-Rus et al, 2006).…”

“…Gene therapy is one approach that has potential as a novel treatment for DMD (Wang et al, 2009). The majority of genetherapy investigations have focused on strategies aimed at restoring dystrophin expression or increasing muscle mass and have been performed in either the mdx mouse (Sicinski et al, 1989) or canine X-linked muscular dystrophy (Valentine et al, 1988;Sharp et al, 1992) models of DMD.…”

Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-Associated Virus (AAV)-5 and AAV-6 in a Large Animal Model

“…AAV-6 is also effective by direct injection into skeletal or cardiac muscle in dogs (Bish et al, 2008;Wang et al, 2009). The experience with AAV-6 in large animals for liver-directed gene transfer is limited.…”

Cell Therapy for Alport Syndrome

“…As a result, critical care nephrology, melding together the expertise of nephrologists and intensivists, has emerged as a distinct subdiscipline during the past decade. [1][2][3] Critical care nephrology is a topic at national and international meetings, has a proposed core curriculum for trainees, 4 and even has its own textbook 5 ; however, a casual perusal of the literature in critical care nephrology rapidly reveals an almost exclusive focus on issues pertaining to acute kidney injury (AKI) with relative neglect of the patient with ESRD and superimposed critical illness. In a nearly 1800-page textbook of critical care nephrology, discussion of critically ill patients with ESRD are covered in fewer than a dozen pages.…”