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Identification of a first in-class integrin enhancing small molecule for the treatment of Duchenne Muscular Dystrophy
AdvisorBurkin, Dean J
Biochemistry and Molecular Biology
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Duchenne muscular dystrophy (DMD) is a catastrophic X-linked neuromuscular disease that affects 1 in every 5000 males. DMD is caused by mutations in the dystrophin gene which results in the loss of dystrophin protein, an essential link between the extracellular matrix and the actin cytoskeleton. This leads to weakened sarcolemmal integrity in the muscle fibers thereby making them susceptible to damage. There is currently no cure for DMD and limited treatment options exist for patients. The α7β1 integrin is an additional laminin-binding heterodimeric protein at the sarcolemma that is elevated in the skeletal muscle of DMD patients and the mdx mouse model. Previous pharmacological and transgenic mouse studies have demonstrated that the α7β1 integrin is a major modifier of disease progression in mouse as well as the Golden retriever dog models of muscular dystrophy. Therefore, we hypothesized that drugs that promote α7β1 integrin expression in muscle could be therapeutic in the treatment of DMD. Utilizing a high-throughput drug discovery chemical screen, we identified SU9516, an adenosine mimetic, as an enhancer of ITGA7 expression, the gene encoding integrin α7. We found SU9516 increased α7B integrin protein levels in C2C12 and immortalized human DMD myotubes. Preclinical studies with oral delivery of 5mg/kg/day SU9516 treatments in the mdx mouse model ameliorated the dystrophic pathology and improved muscle force and function at 10 weeks of age. This thesis presents the therapeutic benefits of a first in-class integrin enhancing small molecule therapeutic SU9516, for the treatment of DMD.