Underdog Pharmaceuticals, Inc. (UDP), in collaboration with the SENS Research Foundation (SRF), aims to demonstratethat 7-ketocholesterol (7KC) is elevated in red blood cells (RBCs) in Atherosclerosis and Alzheimer's disease. 7KC isprimarily created by non-enzymatic oxidation of cholesterol. With only a few exceptions, human tissues lack the ability tometabolize or excrete 7KC. As it is generated by a time-dependent physical process and cannot be removed, 7KCbioaccumulates to higher and higher levels during the aging process. Existing data indicate that 7KC accumulates in theRBCs of heart failure patients; we have extended this finding with preliminary data that show 7KC also accumulates inthe blood of atherosclerosis patients. In this work, we intend to examine the RBC 7KC levels in patients with Alzheimer'sdisease (AD). This will expand the indication space for UDP's proprietary class of engineered cyclodextrins (CDs), whichare capable of selectively binding and removing 7KC from biological systems. We further intend to compare RBC 7KClevels in the pertinent animal models of these two diseases to determine how well the mouse models recapitulate the 7KCbuildup that we believe is the underlying pathological impetus. This will validate these animal models to demonstrate theefficacy and mechanism of action of UDP CDs against atherosclerosis and AD. Finally, we will test proprietary UDP CDsas therapeutics to remove 7KC and relieve the pathology of the given disease in these animal models. This will lay thegroundwork for clinical trials to test the efficacy of UDP CDs to mitigate myriad age-related diseases starting withatherosclerosis 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. Aging ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Atherosclerosis ; Atheroscleroses ; Atherosclerotic Cardiovascular Disease ; atheromatosis ; atherosclerotic disease ; atherosclerotic vascular disease ; Blood ; Blood Reticuloendothelial System ; Blood Cells ; Peripheral Blood Cell ; Cause of Death ; Cells ; Cell Body ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Cholesterol ; Clinical Research ; Clinical Study ; Clinical Trials ; Coronary heart disease ; Coronary Disease ; atherosclerotic heart disease ; coronary disorder ; Cyclodextrins ; Cycloamylose ; Cyclomaltooligosaccharides ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Erythrocytes ; Blood erythrocyte ; Erythrocytic ; Marrow erythrocyte ; Red Blood Cells ; Red Cell ; blood corpuscles ; Excipients ; Foam Cells ; Foundations ; Glucose ; D-Glucose ; Dextrose ; Heart Diseases ; Cardiac Diseases ; Cardiac Disorders ; heart disorder ; Heart failure ; cardiac failure ; Human ; Modern Man ; Industrialization ; macrophage ; MÏ ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Mus ; Mice ; Mice Mammals ; Murine ; oxidation ; Oxides ; Pathology ; Patients ; Polysaccharides ; Glycans ; Research ; Safety ; Science ; Solubility ; Specificity ; Sterols ; Testing ; Time ; Tissues ; Body Tissues ; Translating ; Work ; 7-ketocholesterol ; 3 beta-hydroxycholest-5-en-7-one ; 3beta-hydroxy-5-cholestene-7-one ; 5-cholesten-3 beta-ol-7-one ; 7-oxocholesterol ; Measures ; Drug Delivery Systems ; Drug Delivery ; Site ; repaired ; repair ; Phase ; Ensure ; Supraoptic Vertical Ophthalmoplegia ; Niemann Pick C Disease ; Niemann-Pick Type C ; Niemann-Pick's Disease Type C ; Pick Disease Type C ; Excretory function ; excretion ; Human body ; Human Figure ; Biological Process ; Biological Function ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Collaborations ; Therapeutic ; Shapes ; Diagnostic ; Western World ; human tissue ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; particle ; Physical Phenomena or Properties ; physical process ; success ; Hydrophobicity ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; novel ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Modeling ; Molecular Interaction ; Binding ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Institution ; Address ; Affinity ; Biology of Aging ; Data ; Pathologic ; Process ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Development ; developmental ; age related ; age dependent ; burden of illness ; burden of disease ; disease burden ; years of life lost to disability ; years of life lost to disease ; design ; designing ; innovation ; innovate ; innovative ; human disease ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; efficacy testing ; animal efficacy ; biological systems ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; reduce symptoms ; alleviate symptom ; ameliorating symptom ; decrease symptom ; fewer symptoms ; relieves symptoms ; symptom alleviation ; symptom reduction ; symptom relief ; healthspan ; health-span ; therapeutically effective ;
