R01HL159712

Tmprss2 as a Potential Target for Treatments of COVID-19 and Respiratory Infectious Viruses in Lung - 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 hosts. 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. It can not only help individual patients recover and reduce the number of deaths but also limit the number of positive carriers and thereby curb 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. These systems represent tissues better than cell lines but offer 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 the 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.

Icahn School Of Medicine At Mount Sinai

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 351% from $705,521 to $3,181,082.