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Principal Investigator: Jinjun Shi
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $664,531
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
With the ability to silence individual genes and to drug the ‘undruggable’, RNA interference (RNAi) therapy has
recently shown clinical success by delivering small interfering RNA (siRNA) to the liver for genetic diseases.
However, new delivery strategies will be needed to expand the targeting possibilities of siRNA therapy beyond
the liver for treatment of other diseases like atherosclerotic cardiovascular disease. We have therefore formed a
team with complementary expertise in siRNA delivery and atherosclerosis, and developed a targeted siRNA
delivery strategy to silence calcium/calmodulin-dependent kinase-IIγ (CaMKIIγ), a kinase that is activated in the
macrophages of human and mouse advanced atherosclerotic lesions and promotes progression of clinically
dangerous plaques. We showed that targeted siCamk2g treatment improved plaque stability by reducing necrotic
core area and increasing fibrous cap thickness. Nevertheless, due to the transient nature of siRNA-mediated
gene silencing, a critical challenge for siRNA therapy is the short duration of action. In this project, we propose
to i) explore a novel siRNA delivery strategy that can dramatically extend the duration of CaMKIIγ silencing in
atherosclerotic lesional macrophages; and ii) engineer the new siCamk2g platform for dual-cell targeting for
integrated treatment of obesity-induced type 2 diabetes and atherosclerosis. Our new preliminary work has
identified a distinct type of synthetic lipid-poly(ethylene glycol) (lipid-PEG) biomaterials that can markedly prolong
siRNA silencing and its blood circulation. We thus hypothesize that the new lipid-PEG-mediated long-acting
siCamk2g therapy could effectively target both atherosclerosis and insulin resistance with low dosing frequency.
In Aim 1, we will synthesize a series of such distinct lipid-PEG biomaterials; systematically explore the lipid-PEG
effects on the duration of action and pharmacokinetics of siRNA; and optimize the unique siRNA delivery platform
in a mouse model with established atherosclerosis. The lead candidate with longest duration of macrophage
CaMKIIγ silencing will be evaluated for efficacy in dampening atherosclerosis, with an emphasis on plaque
necrosis, fibrous cap thickness, and efferocytosis and other inflammation resolution endpoints. In Aim 2, we will
expand the long-acting siRNA therapy to dual-cell targeting for cardiometabolic disease, based upon the fact
that CaMKIIγ is a common upstream target in both hepatocytes in obesity-induced insulin resistance and lesional
macrophages in atherosclerosis. We will iteratively optimize the dual-targeting siCamk2g system in vitro and in
vivo, including in a new mouse model with combined insulin resistance and atherosclerosis, in a manner to
effectively improve type 2 diabetes and suppress atherosclerosis. We expect that successful completion of this
project will lead to fundamental understanding of how the new lipid-PEG chemistry controls siRNA delivery and
the development of a novel class of long-acting RNAi therapy for atherosclerosis and cardiometabolic disease.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Acetylgalactosamine><Address><Adult-Onset Diabetes Mellitus><Apoptotic><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Biocompatible Materials><Biomaterials><Blood><Blood Circulation><Blood Clotting><Blood Reticuloendothelial System><Blood coagulation><Bloodstream><Calcium><Calcium-Dependent Activator Protein><Calcium-Dependent Regulator><Calmodulin><Cardiac infarction><Cardiometabolic Disease><Cardiometabolic Disorder><Categories><Cause of Death><Cell Body><Cells><Cessation of life><Chemicals><Chemistry><Chronic Disease><Chronic Illness><Clinical><Collaborations><Complex><Coronary Disease><Coronary heart disease><D-Galactose><Dangerousness><Death><Development><Dihydroxyethanes><Disease><Disorder><Dose><Drug Kinetics><Drugs><Engineering><Ethanediols><Ethylene Glycols><FDA approved><Formulation><Frequencies><Galactopyranose><Galactopyranoside><Galactose><Gene Inactivation><Gene Silencing><Generations><Genes><Genetic Diseases><Goals><Half-Life><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Human><Impairment><In Vitro><Individual><Inflammation><Injections><Insulin Resistance><Ketosis-Resistant Diabetes Mellitus><Kinases><Ligands><Lipids><Liver><Liver Cells><Macrophage><Maturity-Onset Diabetes Mellitus><Mediating><Mediator><Medication><Mice><Mice Mammals><Modeling><Modern Man><Modification><Monoethylene Glycol><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Mφ><N acetylgalactosamine><NIDDM><Nanotechnology><Nature><Necrosis><Necrotic><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><Outcome><Peptides><Phagocytosis><Pharmaceutical Preparations><Pharmacokinetics><Phosphodiesterase Activating Factor><Phosphodiesterase Protein Activator><Phosphotransferase Gene><Phosphotransferases><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><RNA Interference><RNA Interference Therapy><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA interference therapeutics><RNA interference-based therapy><RNA therapy><RNAi><RNAi therapeutics><RNAi therapy><RNAi-based therapeutics><RNAi-based therapy><Resolution><Safety><Science><Sequence-Specific Posttranscriptional Gene Silencing><Series><Short interfering RNA><Slow-Onset Diabetes Mellitus><Small Interfering RNA><Stable Diabetes Mellitus><Surface><System><T2 DM><T2D><T2DM><Technology><Testing><Therapeutic><Thick><Thickness><Transphosphorylases><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Work><adiposity><adult onset diabetes><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic heart disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biological material><cardiac infarct><chronic disorder><clinical development><coronary attack><coronary disorder><coronary infarct><coronary infarction><corpulence><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><determine efficacy><developmental><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><ethylene glycol><evaluate efficacy><examine efficacy><genetic condition><genetic disorder><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><improved><in vivo><in vivo Model><insulin resistant><insulin tolerance><ketosis resistant diabetes><lead candidate><lipid based nanoparticle><lipid nanoparticle><maturity onset diabetes><mortality><mouse model><murine model><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><novel><obesity intervention><obesity therapy><obesity treatment><resolutions><short interfering RNA delivery><siRNA><siRNA delivery><siRNA therapy><siRNA-based therapeutic><siRNA-based therapy><small interfering RNA delivery><success><surface coating><therapeutic RNA><therapeutic siRNA><therapeutic small interfering RNA><therapeutic target><transcriptional silencing><type 2 DM><type II DM><type two diabetes><uptake><vulnerable plaque><western diet><western-style diet><western-type diet>