Characterization of a novel translational model for Becker muscular dystrophy

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DESCRIPTION (provided by applicant): The translation of basic biomedical knowledge to the development of effective therapeutic approaches depends on animal models that accurately reflect human diseases. Duchenne muscular dystrophy (DMD) is caused by expression of a nonfunctional dystrophin protein product while Becker muscular dystrophy (BMD) results from expression of a partially functional protein product or insufficient dystrophin content. Currently, dystrophin-deficient mice and dogs are used to model dystrophinopathies (BDMD). Undoubtedly, these models have contributed substantially to our current understanding of BDMD and development of therapeutic interventions, however, neither represents an ideal model as there are limitations to each. Consequently, there remains a critical need to develop and characterize animal models that more accurately recapitulate the BDMD phenotype observed in humans. We have identified a line of pigs that have a high stress-induced death rate and we have mapped the defect to dystrophin and shown a drastic reduction of dystrophin accumulation in muscles from affected animals. Our long-term goal is to achieve a detailed understanding of BDMD to enable development of effective intervention strategies. Unfortunately, achieving our long-term goal is hindered by limitations in currently available animal models. The objective of this application is to fully characterize a porcine model of BMD that complements and extends the utility of currently available models. Based on our preliminary data, our central hypothesis is that pigs with insufficient dystrophin expression will have a phenotype comparable to moderate to severe BMD as experienced in humans. Our rationale for the proposed research is that the pig is physiologically and phylogenetically more similar to humans than is either the dog or mouse and therefore more accurately reflects disease progression as observed in humans. At the completion of this project we will have: 1) characterized a porcine model of BMD for use in translational research and 2) transmitted the causative mutation to an NIH miniature pig, which will increase its relevance as a translational model. This research is innovative because it focuses on a new animal model, a porcine model of BMD. Further, preliminary data shows the disease phenotype is strongly correlated to a recently discovered single nucleotide polymorphism that results in suppressed dystrophin expression. The proposed research is significant because it will provide characterization of a much needed large animal model that is expected to more closely reflect the human disease than currently available animal models. The expected outcomes of work proposed in aims 1 and 2 is a full characterization of disease progression in skeletal muscle from dystrophin-insufficient pigs as well as an initial validation toward future use as a translational research model for BDMD. Such a model will have an important positive impact in that it will provide researchers with a much needed alternative and comparative model for BDMD research and it may prove to be an invaluable resource for pre-clinical studies.