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

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

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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.

项目摘要该组合阶段I/II SBIR项目的目的是在商业化A中实现关键里程碑贝克尔肌肉营养不良（BMD）的蛋白质治疗方法将增强肌肉细胞的修复能力肌膜膜因肌营养不良蛋白基因中的突变而损害，降低表达水平或肌营养不良蛋白的功能。肌营养不良蛋白基因结果的许多突变可能在BMD中，而其他突变则可以导致更严重的Duchenne肌肉营养不良（DMD）。 Myos Inc.正在开发一种新颖的重组三方蛋白72/mitsugumin 53（TRIM72/mg53）的构建体，膜修复的必要调节剂在骨骼和心脏肌肉中。众所周知，RHMG53治疗可以缓解肌营养不良蛋白的病理不足的小鼠模型和其他肌肉营养不良的模型，强烈表明它可能会增强 BMD中肌肉功能的修复和恢复。但是，最近的潜在毒性问题使得原始 RHMG53蛋白质序列用于蛋白质治疗。因此，我们设计了一个新版本的 RHMG53蛋白用于通过优化其功能和生化特性来治疗BMD。此阶段I/II 项目将通过生成支持研究新的必要数据来进一步开发这种新型蛋白质药物（IND）通过三个特定目标向美国食品药品监督管理局（FDA）申请。目标1意志开发用于生产该蛋白质的化学，制造和控制方案（CMC）方案。优化中国仓鼠卵巢（CHO）细胞培养物的蛋白质产生将以关注的CMO进行 CHO细胞中的蛋白质产生。作为蛋白质的一部分，我们还将对蛋白质进行长达24个月的稳定性测试这个目标的研究。可交付成果将是生产这种蛋白质和生成的规模协议目标2和3的蛋白质。目标2将完成临床前试验，以便该蛋白在治疗A BMD的鼠标模型。该目标将涉及小鼠中三剂蛋白质的临床前疗效试验 BMD的模型。 BMD小鼠的随机队列将进行8-45周的治疗，并发生变化营养不良表型将通过骨骼和心脏肌肉的各种测量来确定结构和功能。该目标的可交付方式是解决蛋白质有效治疗啮齿动物 BMD的模型。 AIM 3将对小鼠蛋白质进行免疫原性和毒性研究。该评估将涉及毒性研究，包括重复剂量研究，毒理学评估，代谢研究和 BALB/C小鼠中的免疫原性评估。这些研究将在myos和一个长长的CRO进行进行此类研究的历史。这里的可交付能力将完成这些研究，以便数据可以是用于指导监管文件。成功完成该项目将产生足够的数据来准备 IND应用于FDA，用于用于治疗BMD的临床试验。