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

用于治疗杜氏肌营养不良症的整合素增强分子的优化

• 批准号: 10010445
• 负责人: DEAN J. BURKIN
• 金额: $ 74.76万
• 依托单位: STRYKAGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10010445
• 关键词: Actins; Adrenal Cortex Hormones; Adult; Affect; Animals; Anti-Inflammatory Agents; Becker Muscular Dystrophy; Binding; Biochemical; Birth; Body Weight; Cardiac; Cardiomyopathies; Cell Nucleus; Clinical Treatment; Clinical Trials; Collaborations; Complex; Creatine Kinase; Cytoskeleton; Data; Development; Digital Radiography; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Duchenne muscular dystrophy; Dystrophin; Effectiveness; Electrocardiogram; Extracellular Matrix; FDA approved; Failure; Fiber; Fibrosis; Gait; Generations; Genes; Glycoproteins; Hand Strength; Histologic; Homologous Gene; Hypertrophic Cardiomyopathy; Incidence; Inflammation; Integrins; Isoproterenol; Kyphosis deformity of spine; Laminin; Lead; Link; Measures; Mechanics; Mediating; Membrane; Molecular; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Mutation; Myocardium; Myopathy; Natural regeneration; Nevada; Pathology; Patients; Pharmacodynamics; Phase; Physiological; Prednisone; Proteins; Publishing; SSPN gene; Safety; Sarcolemma; Scaffolding Protein; Serum; Signal Pathway; Skeletal Muscle; Small Business Technology Transfer Research; Symptoms; System; Technology; Therapeutic; Toxic effect; Toxicology; Transgenic Organisms; Treatment Protocols; Ultrasonography; United States National Institutes of Health; Universities; Utrophin; Viral; Wasting Syndrome; X Chromosome; analog; base; efficacy study; exhaustion; exon skipping; exon skipping therapy; experimental study; functional loss; gene replacement; gene therapy; heart function; improved; in silico; male; mdx mouse; micro-dystrophin; mouse model; muscle degeneration; muscle regeneration; muscle strength; muscular dystrophy mouse model; neuromuscular; novel; overexpression; pre-clinical; preclinical safety; preclinical study; protein complex; pyridine; regenerative; small molecule

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.

抽象的 杜氏肌营养不良症 (DMD) 是一种致命的肌肉疾病，预计男性发病率为五千分之一。 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，负责 在细胞外基质中的肌纤维肌动蛋白细胞骨架和层粘连蛋白之间提供机械连接。 α7β1 整合素是骨骼肌和心肌中的跨膜连接系统，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度表达 α7 整合素可减轻 DMD 小鼠模型的疾病进展并提高其存活率。丢失 7 肌营养不良蛋白缺陷的 mdx 小鼠中的整合素会导致更严重的肌肉疾病。这些研究一起 证明 71 整合素可以作为肌营养不良蛋白丢失的替代物，并且是药物的靶标 为基础的疗法。 Burkin 实验室最近发表了使用 α7 整合素增强化合物的积极结果 SU9516 和舒尼替尼在 DMD mdx 小鼠模型中的应用。结果表明，两种化合物均增加了 α7 营养不良性肌肉中的整合素，导致肌肉再生增强，骨骼肌强度提高， 减少肌纤维损伤。在此第 2 阶段 STTR 提案中，我们建议执行临床前安全性/毒性， 使用我们的先导 α7 整合素增强在 mdx5CV 小鼠中进行药代动力学、药效学和功效研究 小分子，Stryka-969。一种小分子治疗方法可改善营养不良患者的再生和力量 肌肉可以单独使用，也可以与外显子跳跃、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 作为一种新型 α7β1 整合素增强分子走向 IND 和 进入 DMD 患者的临床试验。