Nanoparticles encapsulating a potent cholesterol storage inhibitor as a novel therapeutic to treat Alzheimer's disease

封装有效胆固醇储存抑制剂的纳米颗粒作为治疗阿尔茨海默病的新型疗法

• 批准号: 9898156
• 负责人: Adrianna De La Torre
• 金额: $ 4.55万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2021-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898156
• 关键词: Abeta clearance; Abeta synthesis; Acyl Coenzyme A; Address; Adrenal Glands; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Antibodies; Area; Arginine; Autophagocytosis; Behavioral; Biogenesis; Biological Availability; Blood - brain barrier anatomy; Brain; Cardiovascular Diseases; Cause of Death; Cell Culture Techniques; Cell Line; Cells; Characteristics; Chinese Hamster Ovary Cell; Cholesterol; Cholesterol Esters; Chronic; Clinic; Clinical; Clinical Trials; Cognitive deficits; Combined Modality Therapy; Data; Dementia; Development; Encapsulated; Enzyme-Linked Immunosorbent Assay; Enzymes; Failure; Genetic; Goals; Growth; Half-Life; Histologic; Hour; Human; Hydrophobicity; Intravenous; Learning; Liver; Measures; Mediating; Memory; Methods; Microglia; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oral; Outcome; Pathway interactions; Patients; Penetrance; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Play; Production; Proteins; Provider; Reagent; Role; Senile Plaques; Small Interfering RNA; Sterol O-Acyltransferase; Tauopathies; Testing; Therapeutic; Time; Toxin; Training; Uncertainty; Wild Type Mouse; abeta accumulation; abeta oligomer; base; brain cell; conditioned fear; effectiveness testing; efficacy testing; enzyme activity; extracellular; fighting; improved; in vivo; inhibitor/antagonist; intraperitoneal; mouse model; mutant; nanoparticle; novel; novel therapeutics; rabies virus glycoprotein G; reduce symptoms; responsible research conduct; safety testing; secretase; small molecule; small molecule inhibitor; sterol O-acyltransferase 1; sterol O-acyltransferase 2; success; symposium; tau Proteins; tau aggregation

Abstract Amyloid plaque and tau neurofibrillary tangles are the characteristic hallmarks of Alzheimer’s disease (AD). Recent failed clinical trials focused on targeting secretases involved in the amyloidogenic pathway, which is responsible for forming amyloid plaques. These and other failed trials point to the need for identifying novel target(s) that benefit AD in multiple ways, including the reduction of plaque and tangle production, and the enhanced clearance of misfolded tau, oligomeric amyloid beta (Ab) peptides and other toxins. The brain needs cholesterol to maintain vital functions and the dysregulation of cholesterol in the brain has been suggested to play an important role in AD. A small amount of cholesterol is stored away as cholesterol esters by the enzyme Acyl-CoA:cholesterol acyltransferase1 (ACAT1); however, cholesterol esters cannot substitute the function of cholesterol. Dr. TY Chang’s lab and others have shown that, in mouse models of amyloidopathy and tauopathy, ACAT1 blockage (A1B) provides more cholesterol to brain cells such that cells can fight AD by reducing Ab and misfolded tau and improves memory performance. Mechanistic studies suggest that A1B mainly acts by increasing the clearance of Ab oligomers in microglia, and by increasing the degradation of tau in neurons. These studies suggest that A1B is a promising new therapeutic to treat AD. Compound X is an ACAT1 specific small molecule inhibitor that passed Phase I Clinical Safety Test for treating cardiovascular disease; however, whether Compound X can cross the blood brain barrier to reach the brain interior is unknown. This training plan proposes to test the efficacy of several delivery methods to deliver Compound X as nanoparticles (Nanoparticle X) to the mouse brain. As an option, to increase the bioavailability and half-life of Compound X and to better target the brain, the PEGylated nanomicelle used will be tagged with a neuronal specific tag. Aim 1 will determine the short- and long-term efficacy of Nanoparticle X in inhibiting ACAT activity in the CNS. Wildtype mice will be treated with Nanoparticle X by oral, IP or IV administration and sacrificed at various time points. Aim 2 will test the efficacy of Nanoparticle X, delivered to mice by the optimal method, in ameliorating amyloidopathy/tauopathy and cognitive deficits. An AD mouse model will be treated with Nanoparticle X at asymptomatic, early- and late-symptomatic stages. Ab and tau will be assessed by ELISA and histological methods. Memory improvement will be assessed by a fear conditioning behavioral task. This training plan will determine if ACAT inhibitors encapsulated in nanomicelles are a potential therapy for AD. I have accumulated data in cell culture and in vivo that strongly suggest feasibility. I will continue to be under the guidance of my sponsor team, Drs. Chang and Havrda, and collaborators, Drs. Hoopes, Sporn, and Maurer. I will follow the detailed training plan and take relevant coursework, practice responsible conduct of research, and attend conferences. Dr. Chang will be primary provider for all reagents needed.

抽象的 淀粉样斑块和Tau神经原纤维缠结是阿尔茨海默氏病（AD）的特征标志。 最近的临床试验失败的重点是针对涉及淀粉样蛋白生成途径的分泌酶，这是 负责形成淀粉样斑块。这些和其他失败的试验表明需要识别新颖 以多种方式使广告受益的目标，包括减少牙菌斑和纠缠的生产以及 增强了错误折叠的TAU，低聚淀粉样β（AB）肽和其他毒素的清除。 大脑需要胆固醇来维持重要功能，并且大脑中胆固醇的失调具有 被建议在AD中发挥重要作用。将少量胆固醇储存为胆固醇 通过酶酰基辅酶A酯：胆固醇酰基转移酶1（ACAT1）；但是，胆固醇酯不能 替代胆固醇的功能。 Ty Chang博士的实验室和其他实验室表明，在鼠标模型中 淀粉样病和扭曲性病，ACAT1阻塞（A1B）为脑细胞提供了更多的胆固醇，使细胞 可以通过减少AB和错误折叠的TAU并提高记忆力的性能来打击广告。机械研究 建议A1b主要通过增加小胶质细胞中AB低聚物的清除，并增加 神经元中tau的降解。这些研究表明，A1B是一种有希望的新疗法来治疗AD。 化合物X是ACAT1特定的小分子抑制剂，通过I期临床安全测试 治疗心血管疾病；但是，化合物X是否可以越过血脑屏障才能到达 大脑内饰未知。该培训计划的建议，以测试几种交付方法的效率 化合物X作为纳米颗粒（纳米颗粒X）的小鼠脑。作为选择，增加生物利用度 化合物X的半衰期，为了更好地靶向大脑，使用的纳米胶将标记为 神经元特异性标签。 AIM 1将确定纳米颗粒X抑制的短期和长期效率 CNS中的ACAT活性。野生型小鼠将通过纳米颗粒X治疗口服，IP或IV给药，以及 在各个时间点牺牲。 AIM 2将测试纳米颗粒X的效率，该纳米粒子通过最佳输送到小鼠的效率 方法，改善淀粉样疗法/tauopaty和认知缺陷。 AD鼠标模型将被处理 在无症状，早期和后期症状阶段，纳米颗粒x。 AB和Tau将由 ELISA和组织学方法。记忆改善将通过恐惧调节行为任务来评估。 该培训计划将确定纳米细胞中封装的ACAT抑制剂是否是一种潜在的治疗疗法 广告。我在细胞培养和体内积累了数据，这些数据强烈建议可行性。我将继续 在我的赞助商团队的指导下。 Chang和Havrda和合作者Drs。箍，旋转和 莫勒。我将遵循详细的培训计划，参加相关课程，练习负责任的行为 研究，参加会议。 Chang博士将成为所有需要的试剂的主要提供商。