Document text
Principal Investigator: Clair Crewe
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $622,000
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Project Summary
Current paradigms of drug development have made remarkable progress in treating and
preventing disease by effecting the function of a single target enzyme, or receptor with
specificity. However, many chronic diseases like type 2 diabetes, Alzheimer’s disease, and
cardiovascular disease are multifaceted and may require alterations in multiple pathways, or
delivery to intracellular targets, to effectively treat the condition. For this reason, extracellular
vesicles (EVs) have gained attention as potential therapeutic carriers and endogenous
modulators of disease. EVs are nano-sized vesicles produced in all cells and carry
macromolecules that are capable of modulating multiple pathways simultaneously in the
receiving cell. Their cargo includes miRNAs, mRNA, DNA, signaling proteins, enzymes
metabolites and receptors. Mesenchymal stem cells (MSCs) have been extensively used as the
parent cells for therapeutic EVs as the cargo of these cells is broadly protective. Many groups
have engineered MSC EVs to carry therapeutic compounds through permeabilization techniques
which rely on passive diffusion of compounds into isolated EVs. However, the current
engineering techniques are exceptionally inefficient, which is a major factor in preventing the
translation of engineered EVs into the clinic.
In this proposal we utilize vascular endothelial cells (ECs) to actively package desired
cargo into EVs. This is possible through a novel transcytosis-like process we recently published.
We found that ECs take up exogenous albumin-bound material from the cell culture media, load
the endocytosed material into newly formed EVs, and export those EVs at the basolateral side
of the cell. Interestingly, the released EVs seem to target specific cells in the tissue. Therefore,
we have designed experiments to test and optimize the capacity of ECs to load EVs with
exogenous albumin-bound miRNA, peptides, and drugs. We will test the therapeutic efficacy of
customized EVs in an in vitro and in vivo myocardial infarction mouse model system. We expect
that utilizing ECs will allow for extremely efficient, active loading of EVs, unmatched targeting to
the desired cell type and improved cargo offloading efficiency in receiving cells. This work has
the potential to transform the EV engineering field and bring us closer to clinically applicable EV-
based therapeutics.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><5-Isothiocyanatofluorescein><AD dementia><Adult-Onset Diabetes Mellitus><Albumins><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Attention><Back><Binding><Biologic Models><Biological Models><Biomedical Engineering><Biotech><Biotechnology><Body Tissues><COVID-19 virus><COVID19 virus><Cardiac infarction><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell surface><Cells><Cellular injury><Chronic Disease><Chronic Illness><Clinic><CoV-2><CoV2><Combined Modality Therapy><Culture Media><Cytoplasm><DNA><Deoxyribonucleic Acid><Diffusion><Disease><Disorder><Distal><Dorsum><Drug Targeting><Drugs><Electroporation><Encapsulated><Endothelial Cells><Engineering><Enzyme Gene><Enzymes><Experimental Designs><FITC><Fluorescein-5-isothiocyanate><Gene Transcription><Genetic Transcription><Human><In Vitro><Incubated><Injections><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Investments><Ischemia-Reperfusion Injury><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Ketosis-Resistant Diabetes Mellitus><L Cells><Lipids><Maturity-Onset Diabetes Mellitus><Medication><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Messenger RNA><Methods><Mice><Mice Mammals><Micro RNA><MicroRNAs><Model System><Modern Man><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><Organ><Parents><Pathway interactions><Peptides><Permeability><Pharmaceutical Preparations><Pharmacology><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Primary Senile Degenerative Dementia><Process><Production><Protein Modification><Publishing><RNA><RNA Expression><RNA Gene Products><RNA vaccine><RNA-based vaccine><Receptor Protein><Regulation><Reperfusion Damage><Reperfusion Injury><Research><Research Personnel><Researchers><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Side><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Slow-Onset Diabetes Mellitus><Specificity><Stable Diabetes Mellitus><T2 DM><T2D><T2DM><Techniques><Testing><Therapeutic><Therapeutic Effect><Time><Tissues><Toxic effect><Toxicities><Transcription><Translations><Treatment Efficacy><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vascular Endothelial Cell><Vesicle><Work><Wuhan coronavirus><adiposity><adult onset diabetes><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><cardiac infarct><cardiac ischemia><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disorder><cell culture><cell cultures><cell damage><cell injury><cell type><cellular damage><chronic disorder><clinical applicability><clinical application><clinical translation><clinically translatable><combination therapy><combined modality treatment><combined treatment><common treatment><coronary attack><coronary infarct><coronary infarction><coronary ischemia><coronavirus disease 2019 virus><coronavirus disease-19 virus><corpulence><damage to cells><diffused><diffuses><diffusing><diffusions><drug development><drug discovery><drug/agent><electroporative delivery><experiment><experimental research><experimental study><experiments><extracellular><extracellular vesicles><gene electrotransfer><growth media><hCoV19><heart attack><heart infarct><heart infarction><heart ischemia><improved><in vivo><injury to cells><innovate><innovation><innovative><intervention efficacy><interventional strategy><ischemia injury><ischemic injury><ketosis resistant diabetes><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><macromolecule><maturity onset diabetes><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><miRNA><miRNAs><mouse model><multi-modal therapy><multi-modal treatment><murine model><myocardial ischemia/hypoxia><myocardium ischemia><nCoV2><nano sized><nanoparticle therapy><nanosized><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><parent><pathway><prevent><preventing><primary degenerative dementia><receptor><regenerative><restraint><senile dementia of the Alzheimer type><success><therapeutic efficacy><therapeutic evaluation><therapeutic nanoparticles><therapeutic testing><therapeutically effective><therapy efficacy><transcytosis><translation><type 2 DM><type II DM><type two diabetes><vesicle release><vesicular release>