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Principal Investigator: Zahi A. Fayad
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2020
Award: $815,612
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Atherosclerotic plaque regression as a result of lipid-lowering treatment has been limited at best, with
coronary artery disease (CAD) related event rates remaining unacceptably high.
In this application, we propose that targeted immunomodulation of macrophages will resolve plaque
inflammation and beneficially impacts myocardial infarction-induced monocytosis’ detrimental effects. To that
aim, we have developed novel ‘nanobiologic’, a bioengineered version of our body’s own high density
lipoprotein (HDL) nanoparticle that specifically targets (plaque) myeloid cells6,7. The HDL nanobiologic contains
a small molecule inhibitor (TRAF6i), directed against the binding domain of CD40 on TRAF6, to specifically
block CD40-TRAF6 interactions.
Based on these preliminary data in Apoe–/– mice and nonhuman primates, we propose — in two
independent Specific Aims — TRAF6i-HDL’s application to (i) prevent atherosclerotic plaque aggravation due
to myocardial infarction in Apoe–/– mice and (ii) induce plaque regression in a nonhuman primate
atherosclerosis model.
In Aim 1, we will execute a longitudinal and imaging-guided therapeutic study, involving a one-week high-dose
and a four-week low-dose TRAF6i-HDL regimen in atherosclerotic Apoe–/– mice. In the same mouse model, we
will apply TRAF6i-HDL nano-immunotherapy to prevent plaque aggravation after myocardial infarction, by
preventing the detrimental accumulation of inflammatory monocytes in the vessel wall. In Aim 2, based on our
extensive mouse efficacy data and imaging data in nonhuman primates, we will employ TRAF6i-HDL nano-
immunotherapy to regress established plaques in nonhuman primates. Positron emission tomography with
magnetic resonance imaging (PET/MRI) methods will serve as readouts for TRAF6i-HDL’s in vivo behavior
and therapeutic efficacy.
In light of the promising CANTOS trial data, demonstrating a reduction in recurrent rates in
cardiovascular patients that were treated with a targeted anti-inflammatory therapy, successful completion of
this application’s aims will pave the way for potential clinical translation.
Terms: <Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Apo-E><ApoE><Apolipoprotein E><Apoplexy><Aptitude><Arterial Fatty Streak><Arterial Fatty Streaks><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Behavior><Beta Proprotein Interleukin 1><Binding><Bioassay><Biodistribution><Biologic Assays><Biological Assay><Biomedical Engineering><Blood monocyte><Bp50><Brain Vascular Accident><CD40><CDW40><Cancers><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical><Clinical Evaluation><Clinical Testing><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Data><Disease><Disorder><Dose><Dysfunction><Event><Functional disorder><Gene Expression><HDL><HDL Lipoproteins><Heart Vascular><Heavy Lipoproteins><High Density Lipoproteins><High density lipoprotein><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Image><Immune mediated therapy><Immune system><Immunologically Directed Therapy><Immunology><Immunology procedure><Immunomodulation><Immunotherapy><Impairment><Inflammation><Inflammatory><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><LDL><LDL Lipoproteins><Light><Lipids><Low-Density Lipoproteins><MGC9013><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Modeling><Molecular Interaction><Monocytosis><Multimodal Imaging><Murine><Mus><Myelogenous><Myeloid><Myocardial Infarct><Myocardial Infarction><NMR Imaging><NMR Tomography><Nano immunotherapy><Nanoimmunotherapy><Non-Polyadenylated RNA><Nuclear Magnetic Resonance Imaging><Oncology><Oncology Cancer><PET><PET Scan><PET imaging><PETSCAN><PETT><Patients><Photoradiation><Physiopathology><Placebos><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Pre-Clinical Model><Preclinical Models><Preinterleukin 1 Beta><Process><RNA><RNA Gene Products><Rad.-PET><Recurrence><Recurrent><Regimen><Ribonucleic Acid><Safety><Seminal><Sham Treatment><Specificity><Stroke><TNF Receptor-Associated Factor 6 Gene><TNFRSF5><TNFRSF5 gene><TRAF6><TRAF6 gene><Techniques><Therapeutic Studies><Therapy Research><Time><Translations><Treatment Efficacy><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Zeugmatography><allergic/immunologic body system><allergic/immunologic organ system><alpha-Lipoproteins><antiinflammatory><atheromatosis><atherosclerosis plaque><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><beta-Lipoproteins><bio-engineered><bio-engineers><bioengineering><brain attack><cardiac infarct><cerebral vascular accident><cerebrovascular accident><circulatory system><clinical relevance><clinical test><clinical translation><clinically relevant><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><heart attack><heart infarct><heart infarction><image guidance><image guided><image-based method><imaging><imaging method><imaging modality><immune modulation><immune regulation><immune regulator><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic assay><immunologic assay/test><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vivo><intervention efficacy><longitudinal imaging><macrophage><malignancy><member><migration><monocyte><mouse model><multi-modal imaging><multi-modality imaging><multimodality imaging><murine model><nano particle><nano-biological><nano-sized particle><nanobiologic><nanobiological particle><nanoparticle><nanosized particle><neoplasm/cancer><non-human primate><nonhuman primate><novel><p50><pathophysiology><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical><preclinical><prevent><preventing><programs><recruit><research clinical testing><serial imaging><sham therapy><small molecule inhibitor><success><therapeutic efficacy><therapeutically effective><therapy efficacy><vulnerable plaque>