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Development of Small Molecule Therapies Targeting Regeneration for the Treatment of Duchenne Muscular Dystrophy
AdvisorBurkin, Dean J.
Biochemistry and Molecular Biology
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Duchenne muscular dystrophy (DMD) is a devastating, X-linked, neuromuscular disease that affects 1 in 5,000 male children worldwide. DMD causes severe muscle wasting that confines individuals to wheelchairs and ventilators early on in life. Disease progression leads to pulmonary infections and cardiac failure, ultimately leading to the untimely death of patients. DMD is characterized by mutations in the Dmd gene, resulting in a loss of functional dystrophin protein. The lack of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex (DGC). In the absence of the DGC, the muscle is subject to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic and inflammatory infiltration, calcium dysregulation and rounds of degeneration and regeneration affecting satellite cell populations. Currently, there is no cure for DMD and treatments are scarce. The α7β1 integrin has been implicated in increasing myogenic capacity of satellite cells therefore restoring muscle viability, increasing muscle force and preserving muscle function in dystrophic model mice. Our studies have identified two small molecule therapies capable of increasing α7β1 integrin and halting DMD disease progression. SU9516 was identified using a novel cell-based screen developed in our lab and Sunitinib was discovered as an FDA-approved, structural analog of SU9516. Both small molecules are hereafter characterized as α7β1 integrin enhancers capable of promoting myogenic regeneration. Specifically, Sunitinib stimulates satellite cell activation and increased myofiber fusion via transient inhibition of SHP-2/ERK1/2 and activation of the STAT3 pathway. Treatment with Sunitinib in mdx mice demonstrated decreased sarcolemmal damage via myofiber regeneration and enhanced structural support. Additionally, treatment with Sunitinib decreases fibrotic accumulation in the heart of dystrophic mice, making it an appealing therapeutic for DMD. This study identifies two small molecule compounds capable of halting skeletal muscle disease progression in the mdx mouse model of DMD, Sunitinib also showing potential as a treatment for dystrophic, dilated cardiomyopathy.