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Principal Investigator: Ya-Wen Chen
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $638,230
Funding agency: National Heart Lung and Blood Institute
Project Summary
In early 2020, a new virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), generated headlines due to
its unprecedented rate of transmission. SARS-CoV-2 caused the first reported cases of coronavirus disease 2019 (COVID-19)
in December 2019 and continues to spread worldwide. As a family of RNA viruses, SARS-CoV-2 is prone to mutate at a rate
up to a million times faster than its hosts1,2. These rapid genomic alterations have already generated highly transmissible
variants, and have raised concerns that the virus will evade vaccine-induced immunity. In addition, a large percentage of
the global population remains unvaccinated, due to the challenges of production and mass distribution, vaccine hesitancy,
and pending approval status for patients under age 12. Therefore, an effective antiviral has the potential to relieve suffering
for millions—not only helping individual patients recover and reducing the number of deaths, but also limiting the number
of positive carriers and thereby curbing the spread of the pandemic.
This proposal aims to develop an efficient antiviral to impede the virus’ entry into cells, specifically into lung alveolar type
II (AT2) cells, the stem cells of the distal lung. Thanks to recent studies, we know which “door” (a receptor called ACE2) and
“key” (a protease called TMPRSS2) the virus uses to enter cells. Our goal is to remove the key so the virus cannot open the
door and enter host cells. We will use a conventional air-liquid interface (ALI) culture that is representative of the in vivo
airway and a recently developed 3-dimensional (3D) in vitro lung organoid model that recapitulates many aspects of lung
structure and the cellular environment and that has been used to study respiratory viruses, including SARS-CoV-2. These
systems represent tissues better than cell lines, but offers the benefit of being less complex than tissue explants or animal
models. In addition, we have generated a panel of highly sensitive and specific mouse monoclonal antibodies (mAbs)
directed against TMPRSS2. In preliminary studies, the lead TMPRSS2 mAb, AL20, shows no signs of cytotoxicity with a trend
towards inhibition of SARS-CoV-2 pseudovirus entry in cell lines and in lung organoids. Furthermore, we have identified at
least two serine protease inhibitors (serpins) that form complexes with TMPRSS2, and the presence of these complexes is
inversely correlated with the SARS-CoV-2 infection rate. These findings lead to our hypothesis that targeting TMPRSS2 can
inhibit SARS-CoV-2 viral entry and spread.
To test our hypothesis, we will first test the efficacy of AL20 for blocking the entry of SARS-CoV-2 into AT2 cells in lung
organoids and in airway epithelial cells in ALI cultures, and elucidate the underlying mechanisms. We will then evaluate the
effects of serpins on TMPRSS2 activity and SARS-CoV-2 viral entry and spread. Finally, to explore the feasibility of advancing
AL20 to human trials, we will test humanized AL20 in a SARS-CoV-2 hamster model. Syrian golden hamsters are naturally
susceptible to SARS-CoV-2 infection that recapitulates the clinical, virological, histopathological, and immunological
characteristics of human disease, enabling study of its pathogenesis, transmission, and passive immunization effect.
Transgenic human ACE2 is not required for SARS-CoV-2 infection, ensuring that the cell types infected are highly relevant.
These studies will provide critical insights into the mechanisms whereby TMPRSS2 regulates SARS-CoV-2 entry, and suggest
potential therapeutic candidates against COVID-19. The proposed work has the potential to impact the lives of millions of
individuals affected by COVID-19 and other respiratory viruses, such as influenza A, that use TMPRSS2 to enter cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><3-D><3-Dimensional><3D><ACE2><Age><Air><Animal Model><Animal Models and Related Studies><Antibodies><Apoptosis><Apoptosis Pathway><Binding><Binding Proteins><Body Tissues><COVID-19><COVID-19 S protein><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><COVID-19 infection><COVID-19 predisposition><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 susceptibility><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19 infection><COVID19 virus><CV-19><Case Study><Cell Body><Cell Line><Cell Survival><Cell Viability><Cell surface><CellLine><Cells><Cessation of life><Clinical><Clinical Treatment Moab><CoV-2><CoV2><Complex><Coronavirus Infectious Disease 2019><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cricetinae><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Disease><Disorder><Distal><Drugs><Endocytosis Induction><Ensure><Environment><Epithelial Cells><Epitheliasin Gene><Esteroproteases><Family><Genetic mutation><Goals><Golden Hamsters><Golden Syrian Hamsters><Hamsters><Hamsters Mammals><Human><Human Characteristics><Human Nature><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><In Vitro><Incubated><Individual><Infection><Inflammation><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Lead><Learning><Ligand Binding Protein><Ligand Binding Protein Gene><Liquid substance><Lung><Lung Respiratory System><Lung damage><Lytotoxicity><Mediating><Medication><Mesocricetus auratus><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Mutate><Organoids><Orthomyxovirus Type A><PRSS10><Passive Immunization><Pathogenesis><Patients><Pb element><Peptidases><Peptide Hydrolases><Pharmaceutical Preparations><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Process><Production><Progenitor Cells><Programmed Cell Death><Protease Gene><Proteases><Protein Binding><Proteinases><Proteins><Proteolytic Enzymes><Pulmonary Pathology><RNA Viruses><Receptor Protein><Regulation><Resistance><Respiratory Epithelium><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 entry inhibitor><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 predisposition><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 susceptibility><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scientist><Sequence Alteration><Serine Endopeptidase Inhibitors><Serine Protease Inhibitors><Serine Proteinase Antagonists><Serine Proteinase Inhibitors><Serpins><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 entry inhibitor><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Strains Cell Lines><Structure><Structure of respiratory epithelium><Syrian Hamsters><System><TMPRSS2><TMPRSS2 gene><Testing><Time><Tissues><Transgenic Organisms><Transmission><Type A Influenza><Type II Pneumocyte><Vaccination acquired immunity><Vaccination induced immunity><Vaccines><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><ages><airway epithelium><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><block SARS-CoV-2><block SARS-CoV-2 entry><block severe acute respiratory syndrome coronavirus 2><block severe acute respiratory syndrome coronavirus 2 entry><block viral entry><bound protein><case report><cell type><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 impact><coronavirus disease-19 virus><coronavirus infectious disease-19><cultured cell line><cytotoxicity><determine efficacy><differentiation of pluripotent stem cells><dosage><drug candidate><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><evaluate efficacy><examine efficacy><fluid><genomic alteration><hCoV19><heavy metal Pb><heavy metal lead><hesitant to vaccination><human disease><human pluripotent stem cell><in vivo><individual patient><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><infection rate><inhibit SARS-CoV-2><inhibit SARS-CoV-2 entry><inhibit severe acute respiratory syndrome coronavirus 2><inhibit severe acute respiratory syndrome coronavirus 2 entry><inhibit viral entry><inhibiting antibody><inhibitor><insight><liquid><lung injury><lung pathology><mAbs><model of animal><monoclonal Abs><nCoV2><neutralizing antibody><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><non vaccinated><not vaccinated><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><pandemic><pandemic disease><passive vaccination><pluripotent stem cell differentiation><predisposed to Coronavirus disease 2019><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><rate of infection><receptor><resistant><respiratory><respiratory tract epithelium><respiratory virus><response><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><social role><spike proteins on SARS-CoV-2><stem cells><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><therapeutic candidate><three dimensional><transgenic><transmission process><treat COVID-19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><trend><unvaccinated><vaccination hesitancy><vaccine acquired immunity><vaccine associated immunity><vaccine hesitancy><vaccine hesitant><vaccine-induced immunity><vaccine-induced protection><viral entry blocker><viral entry inhibitor><viral infection><virus infection><virus-induced disease><vulnerable to COVID-19><vulnerable to Coronavirus disease 2019><vulnerable to SARS-CoV-2><vulnerable to Severe acute respiratory syndrome coronavirus 2>