Translational development of recombinant protein therapeutic for LGMD2B

项目摘要 这个第一阶段STTR项目将实现蛋白质治疗剂商业化的关键里程碑， dysferlinopathies，这将提高肌肉细胞膜的修复能力， dysferlin基因dysferlinopathies包括肢带肌营养不良2B型（LGMD 2B），Miyoshi 肌病（MMD 1）和其他罕见的肌病，都表现为成人发病的衰弱性肌肉疾病 以广泛的肌肉损伤和进行性虚弱为特征。所有这些肌病都源于 编码一种重要的肌肉膜修复蛋白dysferlin的基因发生突变。治疗进展 dysferlinopathies的研究受到蛋白质大尺寸的阻碍，这使得基因治疗变得复杂 方法，以及天然dysferlin蛋白的复杂功能。Myos建议开发一种治疗方法， 通过使用dysferlin的关键结合伴侣的蛋白质补充疗法治疗dysferlin病， 基序蛋白72/Mitsugumin 53蛋白（MG 53）。MG 53是骨骼肌细胞膜修复的重要调节因子 以及结合dysferlin并能补偿膜修复中dysferlin损失的心肌。到 为dysferlin病提供蛋白补充治疗，我们将使用重组人MG 53（rhMG 53） 蛋白rhMG 53结合膜损伤位点以增强培养细胞中的膜修复能力， 营养不良的动物模型，当应用于细胞外。基于这些研究，Myos寻求开发 MyoTRIM，rhMG 53的新工程版本，用于治疗dysferlin病。MyoTRIM旨在增强修复 并恢复dysferlin病肌肉受损的膜修复， 其他dysferlinopathy治疗方法的发展。该项目的目标是发展化学， 生产和控制（CMC）方法，以生产MyoTRIM蛋白质，并测试MyoTRIM是否可以 使用两个特定目标拯救dysferlinopathy小鼠模型中的病理学。目标1将开发初始CMC MyoTRIM的程序。目标2将完成MyoTRIM在Bla/J小鼠模型中的临床前试验， dysferlin病。第一阶段项目的成功完成将推动MyoTRIM的商业化， 通过改善肌膜修复来治疗肌营养不良症， 与基因或突变无关。MyoTRIM将提供一个平台技术，以针对其他疾病， 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