Galectin 1: A novel small protein therapy for Duchenne muscular dystrophy

半乳糖凝集素 1：一种治疗杜氏肌营养不良症的新型小蛋白疗法

• 批准号: 8781546
• 负责人: DEAN J. BURKIN
• 金额: $ 21.99万
• 依托单位: STRYKAGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781546
• 关键词: Actins; Adrenal Cortex Hormones; Adverse effects; Affect; Age; Applications Grants; Bacterial Proteins; Binding; Binding Proteins; Biological; Biological Assay; Biological Response Modifier Therapy; Birth; Brain; Canis familiaris; Caring; Cells; Clinical Trials; Collaborations; Complementary DNA; Complex; Control Animal; Cytoskeleton; DNA Sequence; Diagnostic radiologic examination; Digital X-Ray; Disease; Disease Progression; Drug Targeting; Duchenne muscular dystrophy; Dystroglycan; Dystrophin; Dystrophin-Associated Proteins; Escherichia coli; Exclusion; Fibrosis; Flow Cytometry; Galectin 1; Genes; Glycoproteins; Grant; Heart; Histology; Human; Human Cloning; Inflammation; Injection of therapeutic agent; Integral Membrane Protein; Integrins; Ion Exchange; Kidney; Kyphosis deformity of spine; Laminin; Lead; Life Expectancy; Link; Liver; Lung; MM form creatine kinase; Mass Spectrum Analysis; Measures; Mechanics; Mediating; Modeling; Mus; Muscle; Muscle Fibers; Mutation; Myoblasts; Myopathy; Natural regeneration; Pathology; Patients; Phase; Phase I Clinical Trials; Plasmids; Production; Property; Proteins; Recombinants; Relative (related person); Research; Sarcolemma; Scaffolding Protein; Serum; Silver Staining; Skeletal Muscle; Small Business Technology Transfer Research; System; Techniques; Technology; Therapeutic; Tissues; Utrophin; Weight; base; exon skipping; fast protein liquid chromatography; gene repair; gene replacement; grasp; human galectin 1; improved; male; mdx mouse; mouse model; muscle strength; novel; preclinical study; prevent; protein complex; protein expression; public health relevance; research study; small molecule; stem; therapeutic protein

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a fatal muscle disease affecting 1 in every 3500 male births. DMD results from mutations in the gene encoding the dystrophin, a 427 kDa scaffolding protein responsible for providing a mechanical link between the muscle fiber actin cytoskeleton and a transmembrane protein complex called the dystrophin-associated glycoprotein complex (DGC). Although life expectancy for DMD patients has gone up in recent years, the only currently approved treatment remains corticosteroids, which have limited positive effects including inflammation inhibition and counterproductive side effects. Recent research studies have focused on using virally mediated gene replacement, direct gene repair, myoblast cell transfer, small molecule protein enhancement, exon skipping small molecules, and protein therapeutics. The Burkin lab has recently shown that recombinant mouse Galectin-1 is capable of stabilizing and restoring the normal protein levels of dystrophin-associated proteins normally in DMD. Galectin-1 treatment also leads to elevated levels of both utrophin and ?7?1 integrin in skeletal muscle, critical modifying proteins that act to protect the fragile sarcolemmal from damage in the absence of dystrophin. The enhanced sarcolemmal stability leads to a decreased myofiber regeneration and damage. Galectin-1 also functions in muscle to limit inflammation and thereby fibrosis. Finally, Galectin-1 treated mdx mice displayed elevated strength and activity levels relative to controls. Strykagen plans to further develop Galectin-1 protein therapy towards an IND application by producing purified human Galectin-1 protein capable of getting FDA approval for phase I clinical trials. In collaboration with our academic partner the purified recombinant galectin-1 will be used in preclinical studies in the mdx mice to demonstrate muscle protecting properties. Results from this study should lead directly into a phase II STTR grant for preclinical studies in the GRMD dog model of DMD. Together these studies will lead to an IND application with the FDA and clinical trials to develop Galectin-1 protein as a novel treatment for DMD.

描述(由申请人提供)：杜氏肌营养不良症(DMD)是一种致命的肌肉疾病，每3500名男性新生儿中就有一人患病。DMD是由dystrophin编码基因突变引起的，dystrophin是一种427 kDa的支架蛋白，负责在肌肉纤维肌动蛋白细胞骨架和称为dystrophin相关糖蛋白复合体(DGC)的跨膜蛋白复合体之间提供机械连接。尽管近年来DMD患者的预期寿命有所增加，但目前唯一被批准的治疗方法仍然是皮质类固醇，其积极作用有限，包括抑制炎症和适得其反的副作用。最近的研究集中在病毒介导的基因替换、直接基因修复、成肌细胞细胞转移、小分子蛋白增强、外显子跳跃小分子和蛋白质治疗等方面。Burkin实验室最近表明，重组小鼠Galectin-1能够稳定和恢复DMD患者正常Dstrophin相关蛋白的正常蛋白水平。Galectin-1治疗还导致骨骼肌中utroin和？7？1整合素水平升高，这是一种关键的修饰蛋白，在没有dystrophin的情况下保护脆弱的肌膜免受损害。肌膜稳定性增强导致肌纤维再生和损伤减少。Galectin-1还在肌肉中发挥作用，以限制炎症，从而抑制纤维化。最后，Galectin-1处理的MDX小鼠显示出比对照组更高的强度和活动水平。Strykagen计划通过生产能够获得FDA批准进行I期临床试验的纯化的人Galectin-1蛋白，进一步开发Galectin-1蛋白疗法，使之成为IND的应用。与我们的学术伙伴合作，纯化的重组Galectin-1将用于MDX小鼠的临床前研究，以展示肌肉保护特性。这项研究的结果将直接导致临床前的第二阶段STTR拨款 DMD犬GRMD模型的研究总而言之，这些研究将导致FDA将IND应用于临床，并开发Galectin-1蛋白作为治疗DMD的新方法。