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

摘要 Duchenne肌营养不良症(DMD)是一种致命的肌肉疾病，预计发病率为每5000名男性中有1例。 DMD是由Dstrophin基因突变引起的，dystrophin是一种427 kDa的支架蛋白，负责 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。 7β1整合素是骨骼肌和心肌中的一个跨膜连接系统，它还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度表达 7整合素可减缓疾病进展并提高DMD小鼠模型的存活率。7的损失 Dstrophin缺陷的MDX小鼠中的整合素会导致更严重的肌肉疾病。把这些研究放在一起 证明71整合素可以作为Dystrophin丢失的替代物，并且是药物靶点- 以治疗为基础。伯金实验室最近发表了使用7整合素增强化合物的积极结果 SU9516和苏尼替尼治疗DMD的MDX小鼠模型。结果表明，两种化合物均能提高-7 营养不良肌肉中的整合素，导致肌肉再生增强，改善骨骼肌力量和 减少肌纤维损伤。在这个第二阶段的STTR提案中，我们建议执行临床前的安全性/毒性， 我们的先导7整合素增强剂在mdx5Cv小鼠体内的药代动力学、药效学和疗效研究 小分子，Stryka-969。一种改善营养不良患者再生和力量的小分子疗法 肌肉可以单独使用，也可以与外显子跳过、基因编辑或基因治疗技术结合使用。 这项研究的结果将使Stryka-969作为一种新的71整合素增强分子向IND和 进入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.