Optimization of an integrin enhancing molecule for the treatment of Duchenne muscular dystrophy

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Abstract Duchenne Muscular Dystrophy (DMD) is a fatal muscle disease with a predicted incidence of 1 in 5000 males. DMD results from mutations in the gene encoding dystrophin, a 427 kDa scaffolding protein responsible for providing a mechanical link between the muscle fiber actin cytoskeleton and laminin in the extracellular matrix. The 7β1 integrin is a transmembrane linkage system in skeletal and cardiac muscle that also links laminin to the actin cytoskeleton. Studies have demonstrated that transgenic and virally mediated overexpression of the 7 integrin alleviates disease progression and improves survival of mouse models of DMD. Loss of the 7 integrin in dystrophin-deficient mdx mice results in more severe muscle disease. Together these studies demonstrate that the 71 integrin can serve as a surrogate for the loss of dystrophin and is a target for drug- based therapies. The Burkin lab has recently published positive results using 7 integrin enhancing compounds SU9516 and Sunitinib in the mdx mouse model for DMD. Results show that both compounds increase the 7 integrin in dystrophic muscle, leading to enhanced muscle regeneration, improved skeletal muscle strength and decreased myofiber damage. In this Phase 2 STTR proposal, we propose to perform preclinical safety/toxicity, pharmacokinetic, pharmacodynamics, and efficacy studies in mdx5CV mice using our lead 7 integrin enhancing small molecule, Stryka-969. A small molecule treatment that improved regeneration and strength in dystrophic muscle could be used alone or in combination with exon skipping, gene editing or gene therapy technologies. Results from this study will move Stryka-969 as a novel 71 integrin enhancing molecules towards IND and into clinical trials for patients with DMD.