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Principal Investigator: Marco E Zamora
Organization: DREXEL UNIVERSITY
Fiscal Year: 2021
Award: $46,036
Funding agency: National Heart Lung and Blood Institute
Proposal Summary/Abstract
Acute respiratory distress syndrome (ARDS) is an acute inflammation of the lungs. It represents 10% of all
intensive care unit (ICU) admissions in the United States. Despite decades of research and numerous large
clinical trials, there are few treatments for ARDS. This lack of disease-specific therapies is primarily due to
three main factors: First, ARDS patients are “fragile” due to frequent multi-system organ failure, and thus
cannot tolerate drug side effects. Second, ARDS, is very heterogeneous in its underlying pathophysiology, and
thus targeting a single pathway may not be sufficient. Third, the disease has a rapidly developing time course,
meaning that it can activate pathways that actively change patient outcomes in the order of hours.To solve the
above problems, the goal of this proposal is to develop and establish mRNA-loaded nanoparticles (mRNA-
LNPs) that can be targeted to specific cell types and organs, whereupon they can express multiple therapeutic
proteins as a platform technology for ARDS. Our lab has previously utilized three targeting moieties we use to
deliver nanocarriers: monoclonal antibodies binding to PECAM (an endothelial cell surface protein), ICAM
(another surface protein abundant on endothelial cells), and non-immune IgG (hereafter called “IgG”). We have
further shown that nanocarriers covalently coated with anti-PECAM and -ICAM antibodies are directed to the
lungs at levels 300-fold higher than “free drugs” (no carrier) addressing (problem #1), Further, mRNA-loaded
nanoparticles can be loaded with mRNA that encodes for various proteins, targeting various pathways
(problem #2). Additionally, mRNA-LNPs can express a variety of proteins for the length of time (~48 hours)
associated with the high-risk period of acute critical illnesses (problem #3) above. It seemed that we developed
a method to exclusively deliver therapeutics to the lung endothelium, as the standing theory was (without direct
evidence) that lung uptake was due entirely to endothelial cells. However, in pilot experiments, my sponsor and
I became aware that other cells reside in the pulmonary capillaries, marginated neutrophils. We found that
while PECAM coated particles are primarily taken up by the endothelial cells, we interestingly, in a paradigm
shift for the field of targted delivery to the lungs, found anti-ICAM targeted nanocarriers were taken up equally
by endothelial cells and leukocytes. This leads to the two key objectives of this proposal: 1) we want to
understand if with increases in leukocytes during ARDS, there will be a change in the cells that take up and
express anti-CAM targeted mRNA-LNPs and 2) develop a novel class of therapeutics for ARDS. This will be
done via 2 Specific Aims. Aim 1 will investigate the cell types that take up and express mRNA-LNPs both in
human, with ex vivo human lungs, and mouse models of ARDS. Aim 2 will investigate the therapeutic potential
of mRNA-LNPs by leveraging the Ang-Tie pathway to express Angiopoietin-1 to decrease pulmonary capillary
leak and finally testing expression capacity in mouse model as well as with ex vivo human lung. The result of
this project will inform future therapeutic design and develop a new class of therapeutic for ARDS, mRNA-LNP.
Terms: <7S Gamma Globulin><ANG1><ANG1 Gene><ANGPT1><ANGPT1 gene><ARDS><Acute><Acute Disease><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Admission><Admission activity><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar><Ang-2><Ang2><Angiopoietin 1 Gene><Angiopoietin-1><Angiopoietin-2><Angiopoietins><Animal Model><Animal Models and Related Studies><Antibodies><Antigenic Determinants><Assay><Awareness><Basic Research><Basic Science><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Blood Vessels><Blood capillaries><Blood leukocyte><Bronchoalveolar Lavage Fluid><Cell Body><Cell Surface Proteins><Cells><Clinical Treatment><Clinical Treatment Moab><Clinical Trials><Complex><Critical Illness><Critically Ill><Da Nang Lung><Development><Disease><Disorder><Dose><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drug Side Effects><Drug Targeting><Drugs><Dysfunction><ELISA><Endothelial Cells><Endothelium><Enzyme-Linked Immunosorbent Assay><Epitopes><Failure><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Future><Goals><Histology><Hour><Human><Hyperoxia><ICAM><IgG><Immunoglobulin G><Inflammatory><Inhalation><Inhaling><Injury><Innate Immune System><Intensive Care Units><KIAA0003><Knowledge><Length><Leukocyte Count><Leukocyte Number><Leukocytes><Leukocytes Reticuloendothelial System><Liquid substance><Luciferase Immunologic><Luciferases><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Marrow Neutrophil><Marrow leukocyte><Measurement><Measures><Mediating><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Nebulizer><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nucleic Acids><Organ><Organ failure><Pathology><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiopathology><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Problem Solving><Proteins><Publishing><Pulmonary Edema><Recombinants><Research><Role><Route><Serum><Shock Lung><Signal Pathway><Signaling Molecule><Site><Solid><Stiff lung><Surface><Surface Proteins><System><Technology><Testing><Therapeutic><Therapeutic Effect><Time><Transplantation><United States><Up-Regulation><Upregulation><Western Blotting><Western Immunoblotting><White Blood Cell Count><White Blood Cell Count procedure><White Blood Cells><White Cell><acute disease/disorder><acute disorder><capillary><cell type><cytokine><design><designing><developmental><drug/agent><experiment><experimental research><experimental study><flow cytophotometry><fluid><high risk><hyperoxygenation><in vivo><injuries><intercellular cell adhesion molecule><lipid nanoparticle><liquid><lung edema><lung injury><mAbs><mRNA><model of animal><model organism><mortality><mouse model><murine model><nano carrier><nano meter scale><nano meter sized><nano particle><nano particle delivery><nano scale><nano-sized particle><nanocarrier><nanometer scale><nanometer sized><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanoscale><nanosized particle><native protein drug><neutrophil><novel><particle><pathophysiology><pathway><pharmaceutical protein><protein blotting><protein drug agent><protein expression><pulmonary><side effect><small molecule><social role><theories><therapeutic agent development><therapeutic development><therapeutic protein><transplant><trial regimen><trial treatment><uptake><vascular><wet lung><white blood cell><white blood corpuscle>