Translational development of recombinant protein therapeutic for LGMD2B

项目摘要 这个第一阶段的STTR项目将在将一种蛋白质疗法商业化方面实现关键的里程碑 将增强因基因突变而受损的肌肉细胞膜修复能力的铁代谢障碍 脱铁蛋白基因。铁代谢障碍的疾病包括肢体吉勒肌营养不良症2B型(LGMD2B)，Miyoshi 肌病(MMD1)和其他较罕见的肌病，均为成人起病的衰弱肌肉疾病 以广泛的肌肉损伤和渐进性虚弱为特征。所有这些肌病都是由 编码一种重要的肌膜修复蛋白--去铁蛋白的基因突变。治疗进展 蛋白质的大小使基因治疗变得复杂，这阻碍了铁代谢障碍的发生 方法，以及天然去铁蛋白的复杂功能。Myos建议开发一种治疗 利用三方的关键结合伙伴-deferlin的关键结合伙伴 基序蛋白72/Mitsugumin 53蛋白(MG53)。MG53是骨膜修复的重要调节因子 和心肌，它能结合去铁蛋白，并能在膜修复过程中弥补去铁蛋白的损失。至 为铁代谢障碍提供蛋白质补充治疗，我们将使用重组人MG53(RhMG53) 蛋白。RhMG53结合膜损伤部位以增强培养细胞的膜修复能力 应用于细胞外的营养不良动物模型。基于这些研究，Myos试图开发出 MyoTRIM，rhMG53的新型工程化版本，用于治疗病。MyoTRIM旨在加强修复 和恢复受损的膜修复功能障碍的肌肉，提供补充治疗 探讨正在开发中的其他治疗方法。这个项目的目标是发展化学， 制造和控制(CMC)方法生产MyoTRIM，蛋白质并测试MyoTRIM是否可以 用两个特定的目标挽救肾功能障碍小鼠模型的病理学。目标1将开发初始CMC MyoTRIM的程序。Aim 2将在Bla/J小鼠模型上完成MyoTRIM疗效的临床前试验 生育障碍症。这一一期项目的顺利完成将推进MyoTRIM和 通过改进肌膜修复来治疗肌营养不良症，对公众健康产生重大影响， 不受基因或突变影响的。MyoTRIM将提供一种平台技术来针对其他疾病，包括 坏死性细胞死亡。 1

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