Translational development of recombinant protein therapeutic for LGMD2B

LGMD2B 重组蛋白治疗剂的转化开发

• 批准号: 10483343
• 负责人: Noah Weisleder
• 金额: $ 25.95万
• 依托单位: MYOS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483343
• 关键词: Adult; Amino Acid Motifs; Animal Model; Binding; Binding Proteins; Biotechnology; Cardiac; Cardiovascular system; Cell Death; Cell membrane; Cells; Chemistry; Clinical Trials; Collaborations; Complementary therapies; Complex; Cultured Cells; DYSF gene; Data; Development; Disease; Doctor of Philosophy; Dose; Engineering; Escherichia coli; Future; Generations; Genes; Goals; Human; Investigational New Drug Application; Laboratories; Lead; Limb-Girdle Muscular Dystrophies; Measurement; Membrane; Methods; Miyoshi myopathy; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle function; Muscular Atrophy; Muscular Dystrophies; Mutation; Myocardial Infarction; Myocardium; Myopathy; Necrosis; Neurodegenerative Disorders; Neuromuscular Diseases; Ohio; Pathology; Patient-Focused Outcomes; Patients; Persons; Pharmacologic Substance; Phase; Phenotype; Phosphatidylserines; Procedures; Production; Proteins; Protocols documentation; Public Health; Publishing; Randomized; Recombinant Proteins; Recombinants; Research; Rodent Model; Site; Skeletal Muscle; Small Business Technology Transfer Research; Source; Supplementation; TRIM Motif; Technology; Testing; Therapeutic; United States Food and Drug Administration; Universities; base; cohort; commercialization; design; dysferlinopathies; efficacy study; gene therapy; improved; improved outcome; mouse model; muscle physiology; muscular structure; novel; overexpression; preclinical efficacy; preclinical study; preclinical trial; repaired; skeletal; standard of care; therapeutic protein; therapy development; ubiquitin-protein ligase

PROJECT ABSTRACT This Phase I STTR project will accomplish key milestones in commercializing a protein therapeutic for dysferlinopathies that will enhance the repair capacity of muscle cell membranes compromised by mutations in the dysferlin gene. The dysferlinopathies include Limb Girdle Muscular Dystrophy Type 2B (LGMD2B), Miyoshi Myopathy (MMD1) and other, rarer myopathies that all present as adult-onset debilitating muscle diseases characterized by extensive muscle damage and progressive weakness. All these myopathies arise from mutations in the gene encoding an essential muscle membrane repair protein, dysferlin. Progress in treatment of dysferlinopathies has been hampered by the large size of the protein, which complicates gene therapy approaches, and the complex function of the native dysferlin protein. Myos proposes to develop a treatment for dysferlinopathies through protein supplementation therapy using a key binding partner of dysferlin, the tripartite motif protein 72/mitsugumin 53 protein (MG53). MG53 is an essential regulator of membrane repair in skeletal and cardiac muscle that binds dysferlin and can compensate for the loss of dysferlin in membrane repair. To provide protein supplementation therapy for dysferlinopathies, we will use recombinant human MG53 (rhMG53) protein. rhMG53 binds membrane damage sites to enhance membrane repair capacity in cultured cells and dystrophic animal models when applied outside the cell. Based on these studies, Myos seeks to develop MyoTRIM, novel engineered version of rhMG53, to treat dysferlinopathy. MyoTRIM is designed to enhance repair and restore the compromised membrane repair in dysferlinopathy muscle, providing a complementary treatment approach to other dysferlinopathy therapies in development. The objective of this project is to develop Chemistry, Manufacturing, and Control (CMC) methods to produce MyoTRIM,protein and to test whether MyoTRIM can rescue pathology in a dysferlinopathy mouse model using two specific aims. Aim 1 will develop initial CMC procedures for MyoTRIM. Aim 2 will complete pre-clinical trial for MyoTRIM efficacy in the Bla/J mouse model of dysferlinopathy. Successful completion of this Phase I project will advance the commercialization MyoTRIM and provide a significant impact on public health by improving muscle membrane repair to treat muscular dystrophies, independent of gene or mutation. MyoTRIM will provide a platform technology to target other diseases involving necrotic cell death. 1

项目摘要 该一期 STTR 项目将实现蛋白质疗法商业化的关键里程碑 肌肉异常疾病将增强因突变而受损的肌肉细胞膜的修复能力 Dysferlin 基因。肌肉萎缩症包括 2B 型肢带肌营养不良症 (LGMD2B)、Miyoshi 肌病 (MMD1) 和其他较罕见的肌病，均表现为成人发病的衰弱性肌肉疾病 其特点是广泛的肌肉损伤和进行性无力。所有这些肌病都源于 编码重要肌肉膜修复蛋白 Dysferlin 的基因发生突变。治疗进展 蛋白质的大尺寸阻碍了dysferlin病的发展，这使基因治疗变得复杂 方法，以及天然 Dysferlin 蛋白的复杂功能。 Myos 提议开发一种治疗方法 通过使用 Dysferlin 的关键结合伴侣（三方）进行蛋白质补充疗法来治疗 Dysferlin 病 基序蛋白 72/mitsugumin 53 蛋白 (MG53)。 MG53 是骨骼膜修复的重要调节因子 心肌结合 Dysferlin，可以补偿膜修复过程中 Dysferlin 的损失。到 为铁蛋白病提供蛋白质补充疗法，我们将使用重组人 MG53 (rhMG53) 蛋白质。 rhMG53 结合膜损伤位点，增强培养细胞的膜修复能力 当应用于细胞外时，营养不良的动物模型。基于这些研究，Myos 致力于开发 MyoTRIM 是 rhMG53 的新型工程版本，用于治疗生育障碍。 MyoTRIM 旨在增强修复 并恢复铁蛋白病肌肉中受损的膜修复，提供补充治疗 正在开发的其他铁蛋白病疗法的方法。该项目的目标是发展化学， 生产 MyoTRIM 蛋白质并测试 MyoTRIM 是否可以的制造和控制 (CMC) 方法 使用两个特定目标来挽救雄性动物病小鼠模型的病理学。目标 1 将开发初始 CMC MyoTRIM 程序。目标 2 将在 Bla/J 小鼠模型中完成 MyoTRIM 功效的临床前试验 生育障碍。该一期项目的成功完成将推进 MyoTRIM 和 通过改善肌肉膜修复来治疗肌肉营养不良，对公共健康产生重大影响， 与基因或突变无关。 MyoTRIM 将提供一个平台技术来针对涉及其他疾病 坏死细胞死亡。 1