Engineered Cyclodextrins to Address 7-ketocholesterol-Associated Diseases ofAging

工程化环糊精可解决 7-酮胆固醇相关的衰老疾病

• 批准号: 10256433
• 负责人: Matthew Sean O'Connor
• 金额: $ 25.21万
• 依托单位: UNDERDOG PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-05 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256433
• 关键词: 7-ketocholesterol; Address; Affinity; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Atherosclerosis; Binding; Biological Markers; Biological Process; Biology of Aging; Blood; Blood Cells; Cause of Death; Cells; Child; Cholesterol; Clinical Research; Clinical Trials; Collaborations; Coronary heart disease; Cyclodextrins; Data; Development; Diagnosis; Diagnostic; Disease; Drug Delivery Systems; Engineering; Ensure; Erythrocytes; Excipients; Excision; Excretory function; Foam Cells; Foundations; Functional disorder; Glucose; Heart Diseases; Heart failure; Human; Human body; Hydrophobicity; Industrialization; Institution; Measures; Metabolism; Modeling; Mus; Neurodegenerative Disorders; Oxides; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polysaccharides; Process; Research; Safety; Science; Shapes; Site; Solubility; Specificity; Sterols; Supraoptic Vertical Ophthalmoplegia; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Western World; Work; age related; animal efficacy; biological systems; burden of illness; design; efficacy testing; healthspan; human disease; human tissue; innovation; macrophage; mouse model; novel; novel therapeutics; oxidation; particle; physical process; reduce symptoms; repaired; socioeconomics; success; targeted treatment; therapeutically effective

Project Summary/Abstract Underdog Pharmaceuticals, Inc. (UDP), in collaboration with the SENS Research Foundation (SRF), aims to demonstrate that 7-ketocholesterol (7KC) is elevated in red blood cells (RBCs) in Atherosclerosis and Alzheimer’s disease. 7KC is primarily created by non-enzymatic oxidation of cholesterol. With only a few exceptions, human tissues lack the ability to metabolize or excrete 7KC. As it is generated by a time-dependent physical process and cannot be removed, 7KC bioaccumulates to higher and higher levels during the aging process. Existing data indicate that 7KC accumulates in the RBCs of heart failure patients; we have extended this finding with preliminary data that show 7KC also accumulates in the blood of atherosclerosis patients. In this work, we intend to examine the RBC 7KC levels in patients with Alzheimer’s disease (AD). This will expand the indication space for UDP’s proprietary class of engineered cyclodextrins (CDs), which are capable of selectively binding and removing 7KC from biological systems. We further intend to compare RBC 7KC levels in the pertinent animal models of these two diseases to determine how well the mouse models recapitulate the 7KC buildup that we believe is the underlying pathological impetus. This will validate these animal models to demonstrate the efficacy and mechanism of action of UDP CDs against atherosclerosis and AD. Finally, we will test proprietary UDP CDs as therapeutics to remove 7KC and relieve the pathology of the given disease in these animal models. This will lay the groundwork for clinical trials to test the efficacy of UDP CDs to mitigate myriad age-related diseases starting with atherosclerosis and Alzheimer’s disease.

项目概要/摘要 Underdog Pharmaceuticals, Inc. (UDP) 与 SENS 研究基金会 (SRF) 合作，旨在证明 动脉粥样硬化和阿尔茨海默氏病中红细胞 (RBC) 中的 7-酮胆固醇 (7KC) 升高。 主要是由胆固醇的非酶氧化产生的，只有少数例外，人体组织缺乏分解胆固醇的能力。 代谢或排泄 7KC 由于它是由时间依赖性物理过程产生的并且无法去除，因此 7KC 现有数据表明，7KC 在衰老过程中会在生物体内积累到越来越高的水平。 心力衰竭患者的红细胞；我们用初步数据扩展了这一发现，显示 7KC 也在 在这项工作中，我们打算检查阿尔茨海默病患者的红细胞 7KC 水平。 这将扩大 UDP 专有类别的工程环糊精 (CD) 的适应症空间。 能够选择性地结合并从生物系统中去除 7KC 我们进一步打算比较 RBC 7KC。 这两种疾病的相关动物模型中的水平，以确定小鼠模型重演 7KC 的程度 我们认为积累是潜在的病理动力，这将验证这些动物模型以证明这一点。 UDP CD 对抗动脉粥样硬化和 AD 的功效和作用机制 最后，我们将测试专有的 UDP CD。 作为去除 7KC 并缓解这些动物模型中特定疾病的病理学的治疗方法。 为测试 UDP CD 减轻多种与年龄相关的疾病的功效的临床试验奠定基础 动脉粥样硬化和阿尔茨海默病。