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

• 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
• 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

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