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

摘要 杜氏肌营养不良症（DMD）是一种致命的肌肉疾病，预计发病率为1/5000的男性。 DMD是由编码肌营养不良蛋白的基因突变引起的，肌营养不良蛋白是一种427 kDa的支架蛋白， 在肌纤维肌动蛋白细胞骨架和细胞外基质中的层粘连蛋白之间提供机械连接。 β 7β1整联蛋白是骨骼肌和心肌中的跨膜连接系统，其也将层粘连蛋白连接到 肌动蛋白细胞骨架研究表明，转基因和病毒介导的过表达的 β 7整合素加速疾病进展并改善DMD小鼠模型的存活率。失去了107 肌营养不良蛋白缺陷型mdx小鼠中的整联蛋白导致更严重的肌肉疾病。这些研究 证明了β 7 β 1整联蛋白可以作为肌营养不良蛋白丢失的替代物，并且是药物治疗的靶点。 基础疗法。Burkin实验室最近发表了使用α 7整合素增强化合物的积极结果 SU 9516和舒尼替尼在DMD的mdx小鼠模型中的作用。结果表明，两种化合物均增加了 整合素在营养不良的肌肉中，导致增强的肌肉再生，改善的骨骼肌强度， 减少肌纤维损伤。在本2期STTR提案中，我们建议进行临床前安全性/毒性研究， 在mdx 5CV小鼠中使用我们的前导β 7整联蛋白增强剂进行药代动力学、药效学和功效研究。 小分子Stryka-969一种小分子治疗，改善了营养不良的再生和力量， 肌肉可以单独使用或与外显子跳跃、基因编辑或基因治疗技术组合使用。 这项研究的结果将使Stryka-969作为一种新型的β 7 β 1整联蛋白增强分子走向IND， 用于DMD患者的临床试验

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.