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

基本信息

批准号：
9104670
负责人：
DEAN J. BURKIN
金额：
$ 0.51万
依托单位：
STRYKAGEN CORPORATION
依托单位国家：
美国
项目类别：
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/9104670
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 Health 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 research study small molecule stem therapeutic protein

项目摘要

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）：Duchenne肌肉营养不良（DMD）是一种致命的肌肉疾病，每3500个男性出生中有1个。 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脚手架蛋白，负责在肌肉纤维肌动蛋白细胞骨架与跨膜蛋白质络合物之间提供机械联系，称为育肥蛋白相关的糖蛋白复合蛋白（DGC）。尽管近年来DMD患者的预期寿命增加，但目前唯一批准的治疗仍然是皮质类固醇，其积极影响有限，包括炎症抑制和适得其反。最近的研究集中在使用病毒介导的基因置换，直接基因修复，成肌细胞转移，小分子蛋白增强，外显子跳过小分子和蛋白质疗法。 Burkin Lab最近表明，重组小鼠Galectin-1能够稳定和恢复正常的DMD肌营养不良蛋白相关蛋白的正常蛋白质水平。 Galectin-1治疗还导致骨骼肌中的乌托蛋白和7？1整联蛋白的水平升高，在没有肌营养不良蛋白的情况下，对保护脆弱的肌符号的作用进行了批判性修饰蛋白质。增强的肌膜稳定性导致肌纤维再生和损害减少。 Galectin-1在肌肉中还起作用，以限制炎症并因此。最后，Galectin-1处理的MDX小鼠相对于对照组显示出升高的强度和活性水平。 Strykagen计划通过产生能够获得I期临床试验的FDA批准，进一步开发出lectectin-1蛋白治疗来实现IND应用。与我们的学术合作伙伴合作，纯化的重组Galectin-1将用于MDX小鼠的临床前研究中，以证明保护特性。这项研究的结果应直接导致临床前II期STTR授予 DMD的GRMD狗模型的研究。这些研究一起将导致通过FDA和临床试验的IND应用，以开发Galectin-1蛋白作为DMD的新型治疗方法。