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）：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 1 人受到影响。 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，负责在肌纤维肌动蛋白细胞骨架和称为肌营养不良蛋白相关糖蛋白复合物 (DGC) 的跨膜蛋白复合物之间提供机械连接。尽管近年来 DMD 患者的预期寿命有所提高，但目前唯一批准的治疗方法仍然是皮质类固醇，其积极作用有限，包括炎症抑制和适得其反的副作用。最近的研究重点是使用病毒介导的基因替换、直接基因修复、成肌细胞转移、小分子蛋白质增强、外显子跳跃小分子和蛋白质疗法。 Burkin 实验室最近表明，重组小鼠 Galectin-1 能够稳定和恢复 DMD 中肌营养不良蛋白相关蛋白的正常蛋白水平。 Galectin-1 治疗还会导致骨骼肌中肌养蛋白和 ?7?1 整合素水平升高，这是一种关键的修饰蛋白，可在缺乏肌营养不良蛋白的情况下保护脆弱的肌膜免受损伤。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，限制炎症，从而限制纤维化。最后，与对照组相比，Galectin-1 治疗的 mdx 小鼠表现出更高的力量和活动水平。 Strykagen 计划通过生产能够获得 FDA 批准进行 I 期临床试验的纯化人 Galectin-1 蛋白，进一步开发 Galectin-1 蛋白疗法，以实现 IND 申请。与我们的学术合作伙伴合作，纯化的重组半乳糖凝集素-1 将用于 mdx 小鼠的临床前研究，以证明肌肉保护特性。这项研究的结果应直接导致临床前 II 期 STTR 资助 DMD GRMD 狗模型的研究。这些研究将共同向 FDA 提交 IND 申请以及开发 Galectin-1 蛋白作为 DMD 新型治疗方法的临床试验。