PATHOGENIC PATHWAYS AND PRECLINCIAL TESTING IN MOUSE MODELS OF MUSCULAR DYSTROPHY

The muscular dystrophies are marked by progressive muscle degeneration and subsequent maladaptive repair. In the most common childhood form, Duchenne muscular dystrophy (DMD), patients develop weakness of skeletal muscles accompanied by cardiac and respiratory muscle dysfunction. Mouse models of muscular dystrophy replicate the pathological aspects of the human disease. Transforming growth factor beta (TGFβ) has been shown to be elevated in both human and animal models of MD, where it is associated with increased fibrosis and decreased muscle strength function and regeneration. Herein, a pre-clinical assessment of isoform specific anti-TGFβ antibodies was conducted in the mdx/hLTBP4 model, which mirrors the regulation of TGFβ seen in human muscle. These antibodies elicited improved signs of regeneration on histopathology with reduction in fibrosis. A similar pre-clinical trial was also carried out using antibodies to latent transforming growth factor beta binding protein-4 (LTBP4). This approach yielded similar signs of decreased inflammation, increased regeneration and resistance to injury with anti-LTBP4 antibodies. In addition to testing novel approaches to ameliorate disease, I also helped characterize a large cohort of Sgcg null mice that serve as a model for Limb Girdle Muscular Dystrophy 2C. By analyzing echocardiographic data alongside histopathological quantitation, I found correlations between cardiac and muscle outcomes, providing new endpoints for preclinical analysis and identifying the abdominal muscles as important for cardiopulmonary outcomes.