"Development of biglycan as a therapeutic for Duchenne Muscular Dystrophy"

描述（由申请人提供）：该肌肉萎缩症U01转化研究将支持重组人多糖（rhBGN）作为治疗药物的开发，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提案支持的工作基础上，我们已经证明了系统递送的rhBGN可以对抗mdx小鼠的营养不良表型并改善肌肉功能。值得注意的是，当剂量<10mg/kg时，rhBGN间隔3周有效。我们提出了一个4年的开发计划，以生产和验证rhBGN材料，以适应临床试验的使用。该计划将从瞬时转染产生的材料的试点研究扩展到mdx小鼠模型的PK/PD，以及在cGMP条件下由稳定细胞系产生的高度表征的材料的剂量优化。为了最大限度地提高这一过程的效率和速度，这项工作将利用标准化模型和分析方法，并与若干生物开发服务专家供应商合作。我们还招募了在生物制造、测试和监管问题方面拥有丰富专业知识的顾问。

DESCRIPTION (provided by applicant): This U01 Translational Research in Muscular Dystrophy will support the development 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. PUBLIC HEALTH RELEVANCE: In these translational studies we will develop a novel protein therapeutic for Duchenne Muscular Dystrophy. The goal is to take our findings in mouse models of this disease and do the work necessary to test this therapy in boys with this devastating disease. If the proposed work is successful, we will be able to move immediately into Phase I clinical trials.