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Principal Investigator: George Ueda
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2021
Award: $308,875
Funding agency: National Institute of Allergy and Infectious Diseases
Broader Impacts: The current COVID-19 outbreak is a global pandemic with over 45 million cases and
1,200,000 deaths officially reported. Epidemiological data emerging from Italy indicate that 40-96% of COVID-
19 patients admitted into the hospital develop ARDS and sepsis. Developing a functional treatment for these
conditions would also have far reaching impacts beyond this current pandemic, as the underlying pathology can
arise from a multitude of factors.
Overview: The goal of this project is to engineer a Tie2 super-agonistic nanoparticle (NP) and optimize its
production at large scale. Our NPs would be used to treat the lethal symptoms of the current COVID-19 viral
outbreak. Acute respiratory distress syndrome (ARDS) and sepsis are major contributors to COVID-19 mortality.
Currently there are no approved drugs to treat these conditions, because activation of the target receptors cannot
be controlled. To bypass these limitations, we engineered a de novo protein therapeutic that overcomes the
major limitations of manufacturing and rapid regeneration of vascular tissue needed to treat ARDS and sepsis.
Such a technology could mitigate the dangers of COVID infection when patients enter clinics or quarantine. Our
NP super-agonist overcomes the limitations of Ang1, the natural protein that signals through Tie2, which is too
unstable to be used as an effective treatment for ARDS or sepsis. The proposed funding would allow for
immediate development of the NP to improve bioavailability and validation of therapeutic utility in two murine
infection models. We will achieve this in three separate aims: Aim 1: Measure PK/PD, Toxicity and
Immunogenicity of Pegylated Ang1F-NP In Vivo. Aim 2: Validate In Vivo Efficacy of Ang1F NPs in C57Bl/6 mice
infected with H1N1-PR8. Aim 3: Validate Whether Ang1-NPs Reduce Lung Injury in Murine COVID-19/SARS-
CoV-2 Infection.
Intellectual Merit: We aim to develop experimental and technological advances that will have a strong impact
in the fields of structural biology, therapeutic discovery, and clinical medicine. We are working with one of the
few medical branches that have access to the current COVID-19 strain and who are actively developing animal
models to test out therapies prior to clinical trials. The proposed research could be a key solution to reduce the
total number of deaths and enable healthcare professionals to better treat patients suffering from viral outbreaks.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Agonist><Alveolar><Angiopoietin 1 Receptor><Angiopoietin Receptor Tie-2><Animal Model><Animal Models and Related Studies><Binding><Bioavailability><Biologic Availability><Biological Availability><Blood><Blood Circulation><Blood Reticuloendothelial System><Blood Vessels><Bloodstream><Body Tissues><Bypass><C57BL/6 Mouse><CD202B Antigen><COVID><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 crisis><COVID-19 death><COVID-19 epidemic><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 outbreak><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 virus><COVID19><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 crisis><COVID19 death><COVID19 epidemic><COVID19 fatality><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 outbreak><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><CV-19><CV19><Capillary Permeability><Cell Body><Cell Communication><Cell Interaction><Cell-to-Cell Interaction><Cells><Cessation of life><Circulation><Clinic><Clinical Medical Sciences><Clinical Medicine><Clinical Trials><CoV disease><CoV-2><CoV2><Containment><Cytokeratin 18><Da Nang Lung><Data><Death><Development><Disease Outbreaks><Dose><Drug Kinetics><Drugs><Early-Stage Clinical Trials><Endothelial Cells><Endothelial TEK Tyrosine Kinase><Engineering><Epidemiological data><Epidemiology data><Epithelial><Epithelial Cells><Epithelial-Specific Protein Receptor Tyrosine Kinase TIE-2><Esteroproteases><Exhibits><Funding><Future><Goals><H1N1><H1N1 Virus><Half-Life><Health Care Professional><Health Professional><Healthcare professional><Hospitals><Human><Immune><Immunes><In Vitro><Infection><Inflammation><Influenza A Virus, H1N1 Subtype><Italy><Lung Alveolar Epithelia><Lung damage><Measures><Medical><Medication><Membrane><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Natural regeneration><Organ><Outbreaks><PK/PD><Pathology><Pathway interactions><Patients><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Physiologic Availability><Pre-Clinical Model><Preclinical Models><Prior Therapy><Production><Protease Gene><Proteases><Protein Engineering><Proteinases><Proteolytic Enzymes><Pulmonary Pathology><Quarantine><Receptor Protein><Regeneration><Regimen><Regulation><Reporting><Research><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 outbreak><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 outbreak><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sepsis><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Signal Pathway><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Stiff lung><Structure><Symptoms><Syndrome><TEK Tyrosine Kinase><TIE-2 Receptor><TIE-2 Receptor Tyrosine Kinase><TIE-2-RTK><TIE2 Tyrosine Kinase><Technology><Tek Receptor><Testing><The Jackson Laboratory><Therapeutic><Therapeutic Effect><Tie2 Receptor><Tissues><Toxic effect><Toxicities><Transgenic Mice><Tropism><Tunica Interna Endothelial Cell Kinase><Tyrosine-Protein Kinase Receptor TEK><Tyrosine-Protein Kinase Receptor TIE-2><Validation><Vascular Diseases><Vascular Disorder><Vascular Permeabilities><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Wuhan coronavirus><adaptive immunity><airway epithelium><alveolar epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><appropriate dose><blood infection><blood vessel disorder><bloodstream infection><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 outbreak><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cost><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><design><designing><developmental><drug/agent><effective therapy><effective treatment><efficacy study><efficacy validation><epidemiologic data><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><genetic protein engineering><hCoV19><immunogenicity><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><isolation/quarantine><lung injury><lung pathology><lymphocyte trafficking><membrane structure><model of animal><model organism><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nCoV2><nano particle><nano-sized particle><nanoparticle><nanosized particle><native protein drug><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><optimal drug dosage><optimal drug dose><p140 TEK><pandemic><pandemic disease><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pharmaceutical protein><pharmacokinetics and pharmacodynamics><phase I protocol><promoter><promotor><protein design><protein drug agent><receptor><recruit><regenerate><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome-CoV><structural biology><therapeutic candidate><therapeutic protein><trafficking><validate efficacy><vascular><vascular dysfunction><vasculopathy><virus protein><wet lung>