Selection and Development of a Lead Biologic for Treating Mitochondrial Disorders

用于治疗线粒体疾病的先导生物制剂的选择和开发

• 批准号: 9559148
• 负责人: R Blake Hill
• 金额: $ 24.16万
• 依托单位: CYTEGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9559148
• 关键词: Affect; Aging; Agonist; Alzheimer' s Disease; Automobile Driving; Bayesian Analysis; Bezafibrate; Biogenesis; Biological Assay; Blood; Cardiomyopathies; Cells; Chronic progressive external ophthalmoplegia; Clinical; Clinical Trials; Collaborations; DNA Sequence Alteration; DNA biosynthesis; DNA copy number; DNA polymerase gamma; DNA-Directed DNA Polymerase; Data; Data Set; Defect; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Endogenous Factors; Engineering; Evaluation; Excision; Exercise; Genes; Genus Hippocampus; Goals; Government; Heart failure; Hereditary Disease; Impairment; Individual; Intervention; Laboratories; Lead; Link; Malignant Neoplasms; Measures; Metformin; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Mitochondrial Proteins; Modeling; Morphology; Mus; Muscle; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Parkinson Disease; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Pharmacology; Phase; Polymerase; Pre-Clinical Model; Property; Protein Analysis; Protein Engineering; Protein Secretion; Proteins; Proteomics; Quality Control; Respiration; Resveratrol; SIRT1 gene; Serum; Synaptic plasticity; Syndrome; Testing; Therapeutic; Thiazolidinediones; Tissues; Translations; Universities; Wild Type Mouse; Wisconsin; Work; age related; base; cognitive function; early onset; endurance exercise; improved; lead candidate; medical schools; mitochondrial dysfunction; mitochondrial fitness; mouse model; new technology; novel; protein expression; repaired; reverse genetics; sedentary

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.

项目总结/摘要 线粒体功能障碍导致线粒体疾病，并与衰老和神经退行性疾病密切相关。 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 来治疗与年龄相关的衰退。CyteGen的假设是运动会导致血液分泌- 携带的蛋白质，系统性地发挥作用，刺激受损线粒体的清除和健康细胞的富集。 线粒体（mitochondrial fitness）该公司的目标是识别这些蛋白质以开发成生物制剂 这将成为一个治疗与线粒体功能障碍相关的无数疾病的平台。的 发现平台建立在现有的工作，运动逆转线粒体功能障碍的小鼠模型 线粒体疾病在本申请中，候选因子在基于细胞的线粒体DNA中进行测试。 目的1中的呼吸测定，并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）;和白藜芦醇（Sirt 1）]。结果将是一个排名 基于每个候选因子改善呼吸的能力对每个候选因子进行排序。在目标2中，假阳性将是 通过普通的分析来评估线粒体形态学分析、mtDNA拷贝 线粒体质量控制蛋白的数量和表达。这些数据将从名单中筛选出一条线索 用于临床前模型的II期开发和转化为临床试验的生物候选物。