Ceramide Mediates COVID-19 Vascular Injury and ARDS
Abstract
Topic Areas: Acute Respiratory Distress Syndrome (ARDS) is present in >90% of COVID-19 fatalities. Neither antivirals nor the immune modulators used clinically or under investigation target the vascular damage unique to COVID-19-induced ARDS (CoV2-ARDS). Hence, therapies directed at the microvascular lung injury that promotes inflammation and lung edema are lacking. This compelling unmet health need is the core motivation for our work. This proposal is responsive to the Respiratory Health Topic Area and Area of Encouragement. Specifically, with development and/or testing of novel and/or innovative treatments to prevent acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). This proposal also aligns with the Area of Encouragement related to acute and chronic lung injury/disorders due to viral infections, such as SARS-CoV-2. Proposed Research Project: The world continues to face the ongoing COVID-19 pandemic caused by a novel betacoronavirus, SARS-CoV-2. COVID-19 has caused over 600,000 deaths in the U.S. alone. COVID-19 often causes a lethal form of acute lung injury called the Acute Respiratory Distress Syndrome (ARDS), which is present in over 90% of COVID-19 fatalities. Numerous vaccines against SARS-CoV-2 virus have been developed, yet many people remain unvaccinated, and new variants of the SARS-CoV-2 virus may break through vaccine protection. As a result, there is continued need for additional ways to treat or prevent illness and death from COVID-19. This project focuses on the biology of the lung, specifically of ARDS. We seek to better understand the biology leading from SARS-CoV-2 to COVID-19 disease to ARDS. Our aim is to explore the potential to disrupt specific biological targets in the lung, to prevent the progression to ARDS, and thereby prevent COVID-19-related deaths. During SARS-CoV-2 infection, lung cells are stressed, exhibiting structural damage on their surface. This damage can be disrupted using a specific kind of therapeutic molecule. We hypothesize that by disrupting this damage to lung cells, we can prevent ARDS. Our research plan includes experiments to test and verify how lung tissue is damaged by SARS-CoV-2 infection, and how a unique class of therapeutic agent may be employed to disrupt the progression of disease. We will measure the benefits of treatment with the therapeutic agent in mice and hamsters. Applicability and Impact: This study could have profound impact on our ability to directly treat COVID-19, and prevent the kind of lung damage that leads to death. Adding a novel treatment to our arsenal would have transformative scientific and societal impact. In order to treat COVID-19, we must understand the mechanisms of severe disease, respiratory failure, and death. By deciphering these molecular events, we can design, develop, and test more effective therapies. Successful outcome of experiments proposed here could allow for rapid re-deployment of existing clinical candidates for the treatment of CoV2-ARDS. Memorial Sloan Kettering Cancer Center (MSKCC) licensee Ceramedix Holding, LLC is developing two therapeutic candidates that target this specific type of cellular damage. The two therapies are each undergoing preclinical evaluation, in preparation for submission to the U.S. Food and Drug Administration (FDA) for approval for human testing. The therapies being explored in this work also have applications for many diseases that share similar underlying mechanisms, including gastrointestinal acute radiation sickness, diabetic retinopathy, acute graft versus host disease (GvHD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPD), and cystic fibrosis (CF). Thus, this class of therapeutics could be a platform to prevent and treat a host of human diseases. Although the focus of this study is a therapeutic that must be intravenously injected, the same biological mechanism can be accessed using related therapeutics that can be delivered
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210243
Entities
People
- Richard Kolesnick
Organizations
- Sloan-Kettering Institute
- United States Army