Mitochondria targeting for Alzheimer's Disease

线粒体靶向治疗阿尔茨海默病

• 批准号: 10363259
• 负责人: Marcus Laird Forrest
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363259
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease therapy; Animals; Award; Biochemical; Bioenergetics; Biological; Brain; Clinical; Coupling; Defect; Dementia; Development; Dose; Energy Metabolism; Glucose; Glycolysis; Human; Impaired cognition; Ketone Bodies; Laws; Magnetic Resonance Spectroscopy; Medicine; Metabolic; Mitochondria; NADH; Oxaloacetates; Oxidation-Reduction; Parents; Parietal; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase Ib Clinical Trial; Play; Positron-Emission Tomography; Prodrugs; Propylene Glycols; Pyruvate; Reduced Glutathione; Respiration; Role; Scanning; Senile Plaques; Testing; Transgenic Mice; Wild Type Mouse; age related; aged; amyloid pathology; beta-Hydroxybutyrate; brain metabolism; cerebral amyloidosis; fluorodeoxyglucose; glucose metabolism; improved; ketogentic; mitochondrial dysfunction; novel strategies; novel therapeutics

PROJECT SUMMARY OF PARENT AWARD Decreased energy metabolism is an invariant feature of the brains of Alzheimer's disease (AD) patients, yet the specific use of pharmacologic strategies to manipulate energy metabolism in the brain remains relatively untested. We have developed a new approach to treating AD that utilizes fundamental biochemical principles such as the law of mass action, and additionally exploits redox ratios (in particular NAD+/NADH coupling) that gate some bioenergetic fluxes. Our overarching hypothesis is that enhancing brain respiration flux, glycolysis flux, or both will benefit AD patients. We have created new drugs that induce a near-ketogenic state, which we propose will enhance brain metabolism and reduce amyloid pathology. The purpose of this exploratory R21 proposal is test our hypothesis that our new “bioenergetic” drug approach will increase brain energy utilization and reduce amyloid plaque formation in both aged wild-type and transgenic mice. We recently completed a Phase 1B clinical trial of the bioenergetic compound oxaloacetate (OAA) in AD patients with mild dementia (NCT02593318), which showed increased default mode network brain glucose utilization by 18FDG-PET and increased parietal and frontoparietal reduced glutathione on magnetic resonance spectroscopy (MRS) scans. However, enhancement was only seen at the highest doses of 2g/day. We have developed new prodrugs that combine OAA with additional bioenergetic molecules that we propose will enhance ketone bodies and pyruvate levels in the brain, synergistically increasing brain metabolism. Aim 1 will test our hypothesis that prodrugs of OAA and β-hydroxybutyrate (BHB) or propylene glycol (PG) can increase available ketone bodies and pyruvate levels, respectively, and affect brain metabolism. Aim 2 will further test this hypothesis in transgenic mice that have rapid accumulation of amyloid plaques (5xFAD). We will further verify activity in aged wild-type mice, which more accurately recapitulate the whole body (and thus brain) declines in mitochondria function and imbalances in ketone bodies and glucose metabolism. In summary, bioenergetic medicine, i.e. the correction of age-induced mitochondria dysfunction, is a fundamentally different approach to AD therapy from current clinical approaches. The biological studies we propose here could show that there is a firm rationale to develop new clinical drugs that take advantage of multiple bioenergetic mechanisms to reduce brain amyloidosis and age-related brain metabolic decline – spurring development of bioenergetic pharmaceutical approaches.

家长奖项目摘要 能量代谢下降是阿尔茨海默病 (AD) 患者大脑的一个不变特征，但 控制大脑能量代谢的药理学策略的具体使用仍然相对 我们开发了一种利用基本生化原理治疗 AD 的新方法。 例如质量作用定律，并另外利用氧化还原比（特别是 NAD+/NADH 耦合） 我们的首要假设是增强大脑呼吸通量和糖酵解。 通量或两者都会使 AD 患者受益，我们已经创造了诱导近生酮状态的新药。 提议将增强大脑新陈代谢并减少淀粉样蛋白病理。 这个探索性 R21 提案的目的是测试我们的假设，即我们的新“生物能”药物 该方法将增加老年野生型和老年型的大脑能量利用率并减少淀粉样斑块的形成 我们最近完成了生物能量化合物草酰乙酸的 1B 期临床试验。 (OAA) 患有轻度痴呆的 AD 患者 (NCT02593318)，显示默认模式网络大脑增加 18FDG-PET 对葡萄糖的利用以及磁力上顶叶和额顶叶还原型谷胱甘肽的增加 然而，仅在最高剂量 2g/天时才观察到增强。 我们开发了新的前药，将 OAA 与我们建议的其他生物能分子结合起来 将增强大脑中的酮体和丙酮酸水平，协同增加大脑新陈代谢目标1。 将检验我们的假设，即 OAA 和 β-羟基丁酸酯 (BHB) 或丙二醇 (PG) 的前药可以增加 目标 2 将进一步测试这一点。 我们将进一步验证转基因小鼠淀粉样斑块快速积累的假设（5xFAD）。 老年野生型小鼠的活动，更准确地概括了整个身体（以及大脑）的衰退 线粒体功能以及酮体和葡萄糖代谢的不平衡。 总之，生物能量医学，即纠正年龄引起的线粒体功能障碍，是一种 AD 治疗方法与我们目前的临床方法有根本不同。 这里的建议可以表明开发新的临床药物是有充分理由的 多种生物能量机制可减少大脑淀粉样变性和与年龄相关的大脑代谢下降 - 促进生物能药物方法的发展。