Preclinical Testing of a Novel Method to Block TGFbeta Family Proteins in DMD

Duchenne Muscular Dystrophy (DMD) has an estimated prevalence of 1.3- 1.8 per 10,000 males aged 5-24 years of age in the United States (2009). Drug therapy for DMD includes glucocorticoid steroids for ambulatory boys and angiotensin inhibiting compounds. Although these medications slow progression of heart and muscle dysfunction in DMD, they do not cure DMD. Further, the side effect profile from chronic steroid use is intolerable in some patients leading to early discontinuation. Even with prolonged steroid use, DMD boys still lose ambulation. Nonetheless, supportive care for DMD has improved longevity. The absence of cardiomyopathy and a reduction in pulmonary complications, especially pulmonary infections, is associated with a longer lifespan (Kenneson et al., 2010). There are also racial correlates, where African Americans fare less well than other groups. The cause of racial disparities in DMD is not known but may arise from genetic and environmental influences. Environmental factors, including socioeconomic status, support, and access to health care, are also likely to contribute to differences in outcome. Our approach has been to define genetic factors beyond the primary dystrophin gene mutation that also serve as important contributors to disease progression. These genetic modifiers are useful for both prognosis but also point to pathways that can be exploited therapeutically.