Engineered Cyclodextrins to Address 7-ketocholesterol-Associated Diseases ofAging

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.Project Narrative
The proposed project will explore oxidized cholesterol derivatives as causal biomarkers of certain age-related disease:
specifically, we intend to investigate one especially toxic form, 7-ketocholesterol (7KC), and its connection to
atherosclerosis and Alzheimer’s disease. We will use the resulting data to demonstrate efficacy of a novel therapeutic
agent targeting 7KC, as well as to contribute to the understanding of a discrete component of the basic biology of aging.