Internal and External Validation of a Porcine Dystrophinopathy Model

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The translation of basic biomedical knowledge to the development of effective therapeutic approaches depends on validated animal models that accurately reflect human diseases and clinically relevant and valid outcome measures. While it is widely appreciated that dystrophinopathy (BDMD) patients suffer progressive loss of skeletal muscle function, disease etiology is evolving to include significant cardiomyopathy and sudden cardiac death due largely to effective respiratory support therapy. While existing models have been and continue to be useful tools for mechanistic studies and initial discovery investigations, inherent limitations necessitate the continued development of large animal models for translational research. Hence, there is an unmet need to internally and externally validate novel models of BDMD that clearly and predictively recapitulate progressive dysfunction caused by dystrophinopathy as assessed by clinically relevant and validated measures. Our long-term goal is to achieve a detailed understanding of BDMD to enable development and testing of effective interventional strategies. To facilitate these translational studies, we have recently initiated the characterization of a novel, spontaneously occurring porcine BDMD model (exon 41 point mutation). The objective of this application is to perform internal and external validation studies focused on progressive skeletal and cardiac muscle dysfunction in order to insert this spontaneously occurring model into the drug discovery pipeline. This objective is buttressed by strong biological and translational rationale demonstrating a genetic cause of the disease consistent with human disease. Further, our previous work and preliminary data show resultant, progressive skeletal muscle injury and dysfunction, and progressive cardiomyopathy, which are also consistent with human dystrophinopathy. In the internal validation phase of this proposal during R21 Aim 1, we will internally validate objective measures of locomotion and respiratory function during disease progression. In R21 Aim 2 we will also apply well-validated echocardiography and electrophysiology approaches for use in this model as the disease advances. Together with our clinical partner we will determine if our measures have been internally validated. Should that be the case we will proceed to external validation studies. In the R33 phase, to demonstrate predictive validity, we will treat affected pigs with pharmacological agents used widely by BDMD patients. Specifically, to improve skeletal muscle function pigs will be treated with prednisone, and to improve cardiac function pigs will be treated with Lisinopril as both have repeatedly been shown to improve skeletal and cardiac muscle function, respectively. The research proposed in this application is innovative because it aims to internally and externally validate progressive skeletal and cardiac muscle dysfunction in a novel, miniature porcine muscular dystrophy model. This research is significant for drug discovery because it would enable, for the first time, testing of an array of treatment approaches (conventional and gene therapy) in a human-sized model that closely reflects human pathophysiological progression, particularly in the cardiovascular system.