Engineered Cyclodextrins to Address 7-ketocholesterol-Associated Diseases ofAging

项目摘要/摘要 Under Dog制药公司(UDP)与SENS研究基金会(SRF)合作，旨在证明 在动脉粥样硬化和阿尔茨海默病中，7-酮胆固醇(7KC)在红细胞(RBC)中升高。7KC是 主要由胆固醇的非酶氧化产生。除了少数几个例外，人类组织缺乏 代谢或排泄7KC。因为它是由依赖时间的物理过程产生的，不能被移除，7KC 在老化过程中，生物积累到越来越高的水平。现有数据表明，7KC在 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 动脉粥样硬化患者的血液。在这项工作中，我们打算检测阿尔茨海默病患者的红细胞7KC水平 疾病(AD)。这将扩大UDP专有类别的工程环糊精(CDS)的适应症空间， 能够选择性地结合和去除生物体系中的7KC。我们还打算将RBC 7KC 在这两种疾病的相关动物模型中的水平，以确定小鼠模型对7KC的概括程度 我们认为这是潜在的病理动力。这将验证这些动物模型以演示 UDP CDS抗动脉粥样硬化和AD的疗效及作用机制。最后，我们将测试专有的UDP CD 在这些动物模型中，作为去除7KC和减轻给定疾病的病理的治疗药物。这将为 为测试UDP CD缓解各种年龄相关疾病的有效性的临床试验奠定基础，从 动脉粥样硬化和阿尔茨海默病。

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.