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Principal Investigator: Ke Cheng
Organization: COLUMBIA UNIV NEW YORK MORNINGSIDE
Fiscal Year: 2024
Award: $751,983
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Myocardial infarction (MI) happens when the blood flow in one or more coronary vessels are blocked.
Due to the limited regenerative capability of the heart, this can lead to life-threatening heart failure (HF). End-
stage HF usually requires heart transplantation. Stem cells have been studied as promising therapeutics for
cardiac repair post-MI in numerous pre-clinical studies and a variety of clinical trials. However, the translation
of stem cell therapy for heart diseases from bench to bedside is still hampered by cell sources, cell viability,
uncertain delivery efficiency and immune rejection. It has been well established that many types of adult stem
cells exert their beneficial effects mainly through secretion of paracrine factors that promote endogenous heart
repair. In recent years, many in the field including our group have gravitated toward the study of extracellular
vesicles (EVs) released from stem cells, which contain the biologically active components and have
comparable therapeutic effects but minimal immunogenicity, suggesting the possibility of a promising
alternative to stem cell therapies. In the past 8 years, our group has been developing secretome and
exosomes (Exos; 30-150 nm extracellular vesicles)- based therapies for lung and heart diseases, and we have
successfully shown their therapeutic efficacy in several pre-clinical studies. Among them, transplantation of
lung spheroid cells (LSCs) has been advanced to a first-in-man clinical trial in patients with lung fibrotic disease
and LSC-secretome/exosome has recently been approved for ARDS-associated COVID-19. Given the safety
and great regenerative potential of LSC products, we performed RNA sequencing in LSC-Exos and found
various therapeutic miRNAs enriched in them. The most abundant of them, miR-100, were shown to benefit
neovascularization and heart function in several studies. However, most exosome therapies for MI treatment
have their intrinsic limitations, such as the safety and efficiency of delivery routes, deliberately hindered the
clinical feasibility. Moreover, since the half-life of Exos in vivo is short, repeated dosing of exosomes is required
for long-term heart treatment. Our main goal of current proposal is to develop inhalation delivery, as a
repeatable and noninvasive route that may boost the efficacy and translatability of LSC-Exo treatment to MI.
Aim 1. Establish the therapeutic benefits of repeated inhalation delivery of LSC-Exo in a mouse model of MI.
Aim 2. Explore and validate the mechanism of action in LSC-Exo inhalation treatment. Aim 3. Determine the
safety and efficacy of LSC-Exo inhalation treatment in a clinically-relevant porcine model of MI. The
development of inhalable cell-free therapeutics has the potential to revolutionize current regenerative medicine
practice. The results of this project, if successful, are expected to dramatically impact current treatment options
for MI patients. These studies will help validate the use of inhalable exosomes as a new therapeutic modality
for heart disease, and lay the ground for future IND-enabled human trials.
Terms: <Acute Lung Injury><Acute Pulmonary Injury><Acute myocardial infarct><Acute myocardial infarction><After Care><After-Treatment><Aftercare><Alveolocapillary Membrane><American><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Animals><Anterior><Applications Grants><Arteries><Balloon Angioplasty><Blood flow><Blood-Air Barrier><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19/ARDS><COVID19/acute respiratory distress syndrome><Cardiac><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Transplantation><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cause of Death><Cell Body><Cell Survival><Cell Viability><Cells><Cicatrix><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary Vessels><Data><Development><Dose><Echocardiogram><Echocardiography><Family suidae><Fibrosis><Future><Goals><Grant Proposals><Gravitation><Half-Life><Harvest><Heart><Heart Diseases><Heart Grafting><Heart Injuries><Heart Muscle Cells><Heart Transplantation><Heart Vascular><Heart failure><Heart myocyte><Histology><Homing><Hospital Costs><Hospitalization cost><Human><Immune><Immunes><Infarction><Inhalation><Inhalation Therapy><Inhaling><Injury><Ischemia><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><Left><Life><Lung><Lung Diseases><Lung Grafting><Lung Respiratory System><Lung Transplantation><Mediating><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modality><Modern Man><Molecular><Molecular Target><Monitor><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Nebulizer><Organ><Pathway interactions><Patients><Peptides><Percutaneous Transluminal Angioplasty><Pigs><Play><Progenitor Cells><Pulmonary Circulation><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Graft><Pulmonary Transplant><Pulmonary Transplantation><Pulmonary veins><RNA Seq><RNA sequencing><RNAseq><Recovery><Regenerative Medicine><Regenerative pathway><Renal function><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Route><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><Safety><Scars><Single cell seq><Source><Suidae><Surface><Swine><Testing><Therapeutic><Therapeutic Effect><Toxic effect><Toxicities><Transgenic Mice><Translations><Transluminal Angioplasty><Transluminal Arterial Dilatation><Transplantation><Transthoracic Echocardiography><Treatment Efficacy><United States><Vascular Endothelial Cell><adult progenitor><adult stem cell><angiogenesis><atherosclerotic coronary disease><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><cardiac failure><cardiac function><cardiac graft><cardiac infarct><cardiac injury><cardiac ischemia><cardiac repair><cardiomyocyte><cellular targeting><circulatory system><clinical relevance><clinical test><clinical translation><clinically relevant><clinically translatable><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><coronary ischemia><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><developmental><disease of the lung><disorder of the lung><efficacy outcomes><exosome><extracellular vesicles><fibrotic lung disease><fibrotic pulmonary disease><first in man><first-in-human><function of the heart><heart attack><heart disorder><heart function><heart infarct><heart infarction><heart ischemia><heart repair><heart sonography><heart transplant><immunogenicity><improved><in vivo><infarct><injuries><insight><intervention efficacy><kidney function><liver function><loss of function><lung disorder><lung transplant><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><model of animal><mouse model><murine model><myocardial ischemia/hypoxia><myocardium ischemia><nebulization><nebulize><neovascularization><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><paracrine><pathway><pig model><piglet model><porcine><porcine model><post treatment><pre-clinical study><preclinical study><progenitor cell based therapy><progenitor cell therapy><progenitor cell treatment><progenitor therapy><progenitor treatment><pulmonary><regeneration pathway><regeneration potential><regenerative><regenerative potential><research clinical testing><safety study><severe acute respiratory syndrome coronavirus 2 associated ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><single cell next generation sequencing><single cell sequencing><social role><somatic progenitor><somatic stem cell><spheroids><stem and progenitor cell therapy><stem cell based therapy><stem cell derived exosomes><stem cell exosomes><stem cell mediated therapy><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based therapeutic><stem cell-based treatment><stem cells><suid><swine model><systemic inflammation><systemic inflammatory response><therapeutic efficacy><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic outcome><therapy efficacy><therapy outcome><transcriptome sequencing><transcriptomic sequencing><translation><transplant><vesicle release><vesicular release>