Selection and Development of a Lead Biologic for Treating Mitochondrial Disorders

项目摘要/摘要 线粒体功能障碍会导致线粒体疾病，并与衰老和神经退行性变密切相关 帕金森氏症和阿尔茨海默氏症等疾病。最近的发现支持线粒体功能障碍可以 被克服来治疗与年龄相关的衰退。CyteGen的假设是运动诱导血液分泌-- 携带的蛋白质系统地作用于刺激移除受损的线粒体和丰富健康的 线粒体(线粒体适合度)。该公司的目标是识别这些蛋白质，以开发成生物制品 这将成为治疗与线粒体功能障碍相关的无数疾病的平台。这个 Discovery平台建立在运动逆转小鼠模型线粒体功能障碍的现有工作基础上 治疗线粒体疾病。在这个应用中，候选因子是在基于细胞的线粒体中进行测试的 AIM 1中的呼吸测定和评估已知的线粒体生物发生激动剂[苯扎贝特和 格列酮(PPAR激动剂)；二甲双胍和AICAR(AMPK)；以及白藜芦醇(Sirt1)]。结果将是一个排名 根据每个候选因素改善呼吸的能力对其进行排序。在Aim 2中，假阳性将是 通过常规检测来评估线粒体形态分析、mtDNA复制 线粒体质控蛋白的数量和表达。这些数据将把名单筛选到一个领先位置 临床前模型和转化为临床试验的第二阶段开发的生物学候选。

Project Summary/Abstract Mitochondrial dysfunction causes mitochondrial diseases and is tightly linked to aging and neurodegenerative disorders such as Parkinson's and Alzheimer's. Recent discoveries support that mitochondrial dysfunction can be overcome to treat age-related decline. CyteGen's hypothesis is that exercise induces the secretion of blood- borne proteins that act systemically to stimulate removal of damaged mitochondria and enrichment of healthy mitochondria (mitochondrial fitness). The company's goal is to identify these proteins to develop into biologics that would serve as a platform to treat the myriad of diseases associated with mitochondrial dysfunction. The discovery platform builds on existing work that exercise reversed mitochondrial dysfunction in a mouse model for mitochondrial disease. In this application, the candidate factors are tested in a cell-based mitochondrial respiration assay in Aim 1 and evaluated known agonists of mitochondrial biogenesis [bezafibrate and the glitazones (PPAR agonists); metformin and AICAR (AMPK); and resveratrol (Sirt1)]. The results will be a rank ordering of each candidate factor based on their ability to improve respiration. In Aim 2, false positives will be eliminated through commonplace assays to assess mitochondrial morphological analyses, mtDNA copy number, and expression of mitochondrial quality control proteins. These data will winnow the list to a lead biologic candidate for Phase II development in pre-clinical models and translation into clinical trials.