Location: Livestock Bio-SystemsTitle: Porcine models of muscular dystrophy
|SELSBY, JOSHUA - Iowa State University|
|ROSS, JASON - Iowa State University|
|Nonneman, Danny - Dan|
|HOLLINGER, KATRIN - Iowa State University|
Submitted to: ILAR Journal
Publication Type: Review Article
Publication Acceptance Date: 4/6/2015
Publication Date: 5/19/2015
Publication URL: http://handle.nal.usda.gov/10113/60878
Citation: Selsby, J.T., Ross, J.W., Nonneman, D., Hollinger, K. 2015. Porcine models of muscular dystrophy. ILAR Journal. 56(1):116-126.
Interpretive Summary: A variety of animal models have contributed to our understanding of dystrophinopathies and to therapy development. Deficiencies in these models necessitate the development of novel, large animal models as preclinical tools. The pig represents a human-sized animal that shares many anatomical and physiological features with humans including the cardiovascular system, which is of importance for studies related to dystrophinopathies. We have recently described early work characterizing a porcine model with a dystrophin insufficiency and associated muscle injury. We are currently characterizing disease progression and developing techniques to objectively measure physiological outcomes. Because of potential stress-induced sudden death, particular care needs to be taken when working with these animals and must also be considered when performing various measurements and husbandry tasks. This porcine dystrophinopathy model holds tremendous promise as a preclinical model in drug and therapy development.
Technical Abstract: Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression limitations inherent to each of these models has slowed progress on therapy development necessitating the development of novel large animal models. Several porcine dystrophin deficient models have been identified though their disease severity seems to be so severe as to limit their potential contributions to the field. We have recently identified and begun the initial characterization of a porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs have consistently elevated serum creatine kinase activity and, preliminarily, display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Our next steps will be to characterize the effects of dystrophin insufficiency on respiratory and cardiac function as well as gain an improved understanding regarding the molecular mechanism leading to dystrophin insufficiency. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From a husbandry perspective pigs can largely be treated normally, with the understanding that acute stress can lead to sudden death so efforts should be made to minimize this to the extent possible.