Mitochondria targeting for Alzheimer's Disease

线粒体靶向治疗阿尔茨海默病

• 批准号: 10523358
• 负责人: Marcus Laird Forrest
• 金额: $ 5.84万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523358
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Animals; Antioxidants; Biochemical; Bioenergetics; Biological; Biology; Brain; Cell Respiration; Clinical; Clinical Research; Clinical Trials; Coupling; Defect; Dementia; Development; Disease; Dose; Drug Kinetics; Energy Metabolism; Engineering; Esters; Glucose; Glycolysis; Goals; Human; Image; Impaired cognition; In Vitro; Insulin; Ketone Bodies; Ketones; Laws; Link; Longevity; Magnetic Resonance Spectroscopy; Malates; Measures; Medicine; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modality; Mus; NADH; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Oxaloacetates; Oxidation-Reduction; Parietal; Pathology; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase Ib Clinical Trial; Phase Ib Trial; Plasma; Play; Positron-Emission Tomography; Prodrugs; Property; Propylene Glycols; Pyruvate; Reduced Glutathione; Respiration; Rodent; Role; Scanning; Senile Plaques; Site; Symptoms; Testing; Transgenic Mice; Wild Type Mouse; age related; aged; amyloid pathology; beta-Hydroxybutyrate; brain metabolism; cerebral amyloidosis; cognitive function; enantiomer; fasting plasma glucose; fluorodeoxyglucose; glucose metabolism; glucose uptake; improved; in vivo; innovation; ketogenesis; ketogentic; mitochondrial dysfunction; novel strategies; novel therapeutics; preservation; response; spectroscopic imaging

PROJECT SUMMARY 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.

项目总结

项目成果

Conformational Changes and Drivers of Monoclonal Antibody Liquid-Liquid Phase Separation.

单克隆抗体液-液相分离的构象变化和驱动因素。

• DOI: 10.1016/j.xphs.2022.10.017
• 发表时间: 2023
• 期刊: Journal of pharmaceutical sciences
• 影响因子: 3.8
• 作者: Larson,NicholasR;Wei,Yangjie;Cruz,ThayanaAraújo;Esfandiary,Reza;Kalonia,CavanK;Forrest,MLaird;Middaugh,CRussell
• 通讯作者: Middaugh,CRussell