Large Animal Model of Spinal Muscular Atrophy

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DESCRIPTION (provided by applicant): Project summary/abstract: This application proposes the generation of a swine model of Spinal Muscular Atrophy (SMA) (pSMN1-/-; hSMN2) using somatic cell nuclear transfer of gene targeted fetal fibroblasts and breeding. The production of transgenic animals has proven tremendously beneficial to our understanding of human disease. Gene targeting using murine embryonic stem cells is the most developed and utilized approach and has provided models of human diseases including SMA. Our understanding of disease processes and gene function could not have occurred without these mouse models. However, increasing evidence in a variety of translational fields including drug discovery and gene and stem cell therapies suggest that large animal models provide more relevant "tools" for the discovery and testing of therapeutics for neuromuscular, neurodegenerative as well as other diseases [38, 55, 62-69]. Spinal Muscular Atrophy (SMA) is a neurodegenerative disease whose translational studies would greatly benefit from the development of a large animal model. As the SMA field moves into more translational studies, one critical question is how our current knowledge obtained from cellular models and small animal SMA models translate into human therapies. It has become increasingly evident in SMA translational studies that critical questions need to be experimentally addressed, including: the best methodology, location and the maximum effective dose to deliver a given therapeutic and its effectiveness. A larger SMA animal would provide an excellent experimental tool to begin to systematically address these questions. Lastly, one of the vexing complications with SMA mice models is the relatively short window of disease progression when considering SMA therapies. The pig animal model will more likely recapitulate the therapeutic window for the human disease. Swine are exceptionally well-suited transgenic models for a number of critical reasons. From a physical standpoint, the scale of the animal and the human and swine metabolisms and organ systems are remarkably similar as well having more similar lifespans, suggesting that the therapies will more likely be directly translated into the human context. For example, the length from the spinal cord to a limb muscle in the swine is more similar to a child than that of a mouse. Additionally, the larger size of the swine permits more direct manipulations (surgical and biochemical) that may be required for some human therapies. It is important to stress that this proposal does not imply that any of the current SMA models are deficient, rather a large animal model of SMA will allow us to address new and distinct questions focused on the development and screening of efficacious therapeutics. And while not the primary rationale for this proposal, a large pig SMA model will allow the study of therapeutic safety and toxicology before clinical trials. PUBLIC HEALTH RELEVANCE: As the Spinal Muscular Atrophy (SMA) field moves into more translational studies one critical question is how our current knowledge obtained from cellular models and small animal models translate into human therapies. This proposal is aimed at developing a large animal model of SMA model in order to better understand the effectiveness of drug, stem cell and gene therapies. Pigs are well-suited animal models for a number of critical reasons including the similarity between human and pig metabolism and organ systems; therefore the development of a pig SMA model would provide unique benefits for the SMA community as the field pushes toward a cure.