Engineered Cyclodextrins to Address 7-ketocholesterol-Associated Diseases ofAging

项目总结/摘要 Underdog Pharmaceuticals，Inc. (UDP)与SENS研究基金会（SRF）合作，旨在展示 在动脉粥样硬化和阿尔茨海默病中，红细胞（RBC）中的7-酮胆固醇（7 KC）升高。7 KC是 主要由胆固醇的非酶促氧化产生。除了少数例外，人体组织缺乏 代谢或排泄7 KC。由于它是由一个时间依赖的物理过程产生的，不能被去除， 在衰老过程中生物积累到越来越高的水平。现有的数据表明，7 KC积累在 心力衰竭患者的红细胞;我们用初步数据扩展了这一发现，表明7 KC也在 动脉粥样硬化患者的血液。在这项工作中，我们打算检查老年痴呆症患者的RBC 7 KC水平 疾病（AD）。这将扩大UDP专有的工程环糊精（CD）类的适应症空间， 能够选择性地结合并从生物系统中去除7 KC。我们还打算比较RBC 7 KC 这两种疾病的相关动物模型中的7 KC水平，以确定小鼠模型重现7 KC的程度 我们认为这是潜在的病理动力。这将验证这些动物模型，以证明 UDP CD抗动脉粥样硬化和AD疗效和作用机制。最后，我们将测试专有的UDP CD 在这些动物模型中作为治疗剂去除7 KC并减轻给定疾病的病理。这将奠定 为临床试验奠定基础，以测试UDP CD减轻无数与年龄有关的疾病的疗效， 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.