Engineered Cyclodextrins to Address 7-ketocholesterol-Associated Diseases ofAging

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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.