Membrane repair as a therapeutic intervention for treating Becker Muscular Dystrophy

膜修复作为治疗贝克尔肌营养不良症的治疗干预措施

基本信息

批准号：
10761285
负责人：
Noah Weisleder
金额：
$ 29.55万
依托单位：
MYOS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761285
关键词：
Acceleration Amino Acid Motifs Amino Acid Sequence Becker Muscular Dystrophy Binding Binding Proteins Biochemical Biological Assay Biotechnology Cardiac Myocytes Cardiovascular system Cell Culture Techniques Cells Cessation of life Chemistry Chinese Hamster Ovary Cell Clinical Clinical Treatment Clinical Trials Collaborations Compensation Complementary therapies Cultured Cells Cytoskeletal Proteins Data Development Disease Doctor of Philosophy Dose Duchenne muscular dystrophy Dystrophin Engineering Escherichia coli Future Generations Genes Genetic Diseases Goals Heart Injuries Human Inbred BALB C Mice Investigational New Drug Application Knockout Mice Laboratories Letters Link Measurement Medical Membrane Metabolism Methods Modeling Mus Muscle Muscle Cells Muscle Development Muscle function Muscular Atrophy Muscular Dystrophies Mutation Myoblasts Myocardium Myopathy Ohio Pathology Patient-Focused Outcomes Patients Pharmacologic Substance Phase Phenotype Phosphatidylserines Predisposition Procedures Production Property Proteins Protocols documentation Randomized Recombinants Recording of previous events Research Rodent Model Site Skeletal Muscle Small Business Innovation Research Grant Source TRIM Motif Therapeutic Therapeutic Intervention Toxic effect Toxicokinetics United States Food and Drug Administration Universities Work clinical development cohort commercialization dysferlinopathies efficacy testing efficacy trial immunogenicity improved improved outcome interest manufacture metabolic abnormality assessment mouse model muscle physiology muscular structure novel novel therapeutics overexpression preclinical efficacy preclinical trial professor protein function repaired restoration scale up skeletal stability testing success technology platform therapeutic protein therapy development ubiquitin-protein ligase

项目摘要

PROJECT ABSTRACT The goal of this combined Phase I/II SBIR project is to accomplish key milestones in commercializing a protein therapeutic for Becker muscular dystrophy (BMD) that will enhance the repair capacity of muscle cell sarcolemmal membranes compromised by mutations in the dystrophin gene that reduce the expression level or function of the dystrophin protein. Many mutations in the dystrophin gene result can in BMD while others result in the more severe Duchenne muscular dystrophy (DMD). Myos Inc. is developing a novel recombinant construct of the tripartite protein 72/mitsugumin 53 (TRIM72/MG53), an essential regulator of membrane repair in skeletal and cardiac muscle. It is known that rhMG53 therapy ameliorates disease pathology in a dystrophin deficient mouse model and models of other muscular dystrophies, strongly suggesting that it may enhance repair and restoration of muscle function in BMD. However, recent potential toxicity concerns make the original rhMG53 protein sequence suboptimal for protein therapy. Therefore, we engineered a new version of the rhMG53 protein for use in treating BMD by optimizing its functional and biochemical properties. This Phase I/II project will further develop this novel protein by producing the data necessary to support an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) through three specific aims. Aim 1 will develop Chemistry, Manufacturing, and Control (CMC) protocols for production of this protein. Optimization of protein production from Chinese Hamster Ovary (CHO) cell cultures will be conducted at a CMO focused on protein production in CHO cells. We will also conduct stability testing up to 24 months for the protein as part of the studies in this aim. The deliverables will be a scale-up protocol for production of this protein and generation of protein for aims 2 and 3. Aim 2 will complete a pre-clinical trial for the efficacy of this protein in treating a mouse model of BMD. This aim will involve a preclinical efficacy trial for three doses of the protein in a mouse model of BMD. Randomized cohorts of BMD mice will be treated with for 8-45 weeks and changes in the dystrophy phenotype will be determined through various measurements of skeletal and cardiac muscle structure and function. The deliverable for this aim will be to resolve if the protein can effectively treat a rodent model of BMD. Aim 3 will conduct immunogenicity and toxicity studies for protein in mice. This assessment will involve toxicity studies, including repeated-dose studies, toxicokinetic assessment, metabolic studies and immunogenicity assessment, in BALB/c mice. These studies will be conducted at Myos and a CRO with a long history of conducting such studies. The deliverable here will be completing these studies so the data can be used to guide regulatory filings. Successful completion of this project will result in sufficient data to prepare an IND application to the FDA for use in clinical trials for the treatment of BMD.

项目摘要这一联合第一阶段/第二阶段 SBIR 项目的目标是实现商业化的关键里程碑贝克型肌营养不良症 (BMD) 的蛋白质治疗剂可增强肌肉细胞的修复能力肌膜因抗肌营养不良蛋白基因突变而受损，表达水平降低或肌营养不良蛋白的功能。抗肌营养不良蛋白基因的许多突变会导致 BMD，而其他突变则可能导致 BMD 导致更严重的杜氏肌营养不良症（DMD）。 Myos Inc. 正在开发一种新型重组三联蛋白 72/mitsugumin 53 (TRIM72/MG53) 的构建体，膜修复的重要调节因子在骨骼肌和心肌中。众所周知，rhMG53 疗法可改善肌营养不良蛋白的疾病病理学缺陷小鼠模型和其他肌营养不良症模型，强烈表明它可能增强修复和恢复 BMD 中的肌肉功能。然而，最近潜在的毒性问题使得最初的 rhMG53 蛋白序列对于蛋白治疗来说不是最佳的。因此，我们设计了一个新版本 rhMG53 蛋白通过优化其功能和生化特性用于治疗 BMD。本期I/II期项目将通过产生支持研究性新蛋白质所需的数据来进一步开发这种新型蛋白质通过三个具体目标向美国食品和药物管理局 (FDA) 提交药物 (IND) 申请。目标1将制定用于生产该蛋白质的化学、制造和控制 (CMC) 方案。优化中国仓鼠卵巢 (CHO) 细胞培养物的蛋白质生产将在 CMO 进行，重点关注 CHO 细胞中的蛋白质生产。我们还将对该蛋白质进行长达 24 个月的稳定性测试，作为为此目的而进行的研究。交付成果将是该蛋白质生产和生成的放大方案目标 2 和 3 的蛋白质。目标 2 将完成一项临床前试验，以确定该蛋白质在治疗小鼠 BMD 模型。该目标将涉及在小鼠体内进行三种剂量的蛋白质的临床前功效试验 BMD 模型。随机分组的 BMD 小鼠将接受 8-45 周的治疗，并观察营养不良表型将通过骨骼和心肌的各种测量来确定结构和功能。该目标的成果将是解决该蛋白质是否可以有效治疗啮齿动物 BMD 模型。目标 3 将在小鼠体内进行蛋白质的免疫原性和毒性研究。此次评估将涉及毒性研究，包括重复剂量研究、毒代动力学评估、代谢研究和 BALB/c 小鼠的免疫原性评估。这些研究将在 Myos 和一家拥有长期研究经验的 CRO 进行进行此类研究的历史。这里的交付成果将是完成这些研究，以便数据可以用于指导监管备案。该项目的成功完成将产生足够的数据来准备向 FDA 申请用于治疗 BMD 的临床试验的 IND 申请。