Development of biglycan as a therapeutic for Duchenne Muscular Dystrophy

开发双聚糖治疗杜氏肌营养不良症

基本信息

批准号：
8382246
负责人：
JUSTIN R. FALLON
金额：
$ 133.65万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8382246
关键词：
Animals Biochemical Biodistribution Biologic Development Biological Assay Biology Build-it Cell Line Cell surface Cells Clinical Data Clinical Trials Collaborations Consult Core Facility Cyclic GMP Data Development Development Plans Disease Dose Drug Exposure Drug Kinetics Duchenne muscular dystrophy Extracellular Matrix Proteins Goals Grant Histopathology Human Immune response Immunology procedure Laboratories Macaca fascicularis Measurement Methods Modeling Monitor Muscle Muscle Cells Muscle function Muscular Dystrophies Pennsylvania Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Phenotype Physiology Pilot Projects Plasma Process Production Proteins Rattus Recombinants Research Rivers Role Route Sarcolemma Services Solutions Staging Testing Therapeutic Toxicology Transfection Translational Research Universities Up-Regulation Utrophin Validation Vendor Work biglycan boys cGMP production cell bank experience improved mdx mouse meetings mouse model novel pre-clinical processing speed protein structure response stable cell line therapeutic protein translational study

项目摘要

This U01 Translational Research in iVluscular Dystrophy will support the deveiopment of recombinant human biglycan (rhBGN) as a therapeutic and to prepare the data package necessary for an IND filing with the FDA. It builds upon work supported by an exploratory R21 proposal to our laboratory where we have demonstrated that systemically-delivered, rhBGN counters the dystrophic phenotype in mdx mice and improves muscle function. Notably, rhBGN is effective when delivered at 3 week intervals and at doses of <10mg/kg. We propose a 4 year development plan to produce and to validate rhBGN material that is compatible with use in clinical trials. This plan will extend from pilot studies with material produced by transient transfection, to PK/PD in the mdx mouse model, to dose optimization with highly characterized material produced from a stable cell line under cGMP conditions. To maximize the efficiency and speed of this process, the work will make use of standardized models and assays as well as collaborations with several expert vendors of biologic development services. We have also enlisted consultants who have extensive expertise in the manufacturing, testing and regulatory issues that are unique to biologies.

U01 肌营养不良症转化研究将支持重组人的开发 biglycan (rhBGN) 作为一种治疗药物，并准备向 FDA 提交 IND 申请所需的数据包。它建立在我们实验室的探索性 R21 提案支持的工作之上，我们已经证明系统递送的 rhBGN 可以对抗 mdx 小鼠的营养不良表型，并且改善肌肉功能。值得注意的是，rhBGN 在每 3 周间隔一次且剂量为 <10毫克/公斤。我们提出了一个 4 年开发计划来生产和验证 rhBGN 材料与临床试验中的使用兼容。该计划将从试点研究延伸，使用由瞬时转染、mdx 小鼠模型中的 PK/PD、高度表征的剂量优化在 cGMP 条件下由稳定细胞系生产的材料。最大限度地提高效率和速度在此过程中，工作将利用标准化模型和分析以及与多家生物开发服务专家供应商。我们还聘请了具有以下经验的顾问：在生物制品特有的制造、测试和监管问题方面拥有丰富的专业知识。