Preclinical Development of a New Kinase Inhibitor for Postviral Lung Disease
Abstract
Respiratory viral infection is a leading cause of morbidity and mortality throughout the world, and the current viral pandemic with SARS-CoV-2 infection has become the third leading cause of death in the U.S. This type of infection can cause acute lung injury with rapid respiratory failure but can also trigger a subsequent set of problems that we designate post-viral lung disease (PVLD). In the case of SARS-CoV-2 infection, PVLD can develop in the short term with devastating respiratory failure or in the long term (so-called long-COVID) with less mortality but still debilitating respiratory symptoms. In both cases, these later forms of disease are extremely common. Thus, we routinely observe progressive disease in the intensive care unit (ICU) setting consistent with our experimental findings. Further, the subset of long-COVID patients already represents 52%-72% of 37 million existing cases, and future cases are currently growing at 150,000 cases per day in the U.S. Moreover, respiratory viral infection and PVLD cause problems that are distinct to military health and readiness. These problems include high levels of close-contact and low-mask conditions, exposure to unvaccinated populations, and high rates of preexisting lung disease in active military and Veteran populations that represent a risk factor for developing more severe PVLD. Despite the personal, economic, and national security impacts of PVLD, there are currently no drug treatments that address the underlying cause of this disease and thereby change how it might develop or persist. Current therapeutics (including vaccines, antibodies, and antivirals) cannot fully address the issue as evidenced by continuing morbidity and mortality despite these approaches. In general, available drugs were developed for other types of diseases and do not necessarily translate to correcting PVLD. Thus, attempts at repurposing drugs have provided little benefit to date. To respond to this unmet need will require a new understanding of how PVLD develops and how to use this insight to develop a new treatment for this type of disease. We also need to know how to guide this treatment for each individual patient to achieve what is commonly labeled as personalized or precision medicine. Based on this reasoning, our project directly addresses these critical issues as follows: 1. How we can define the root cause of PVLD to guide a new treatment. We spent nearly 40 years studying patients with lung disease and experimental models of this disease to finally arrive at a new understanding of how lung disease develops after viral infection. Two major breakthroughs allowed for this insight. First, we realized that a simple respiratory viral infection in a susceptible individual could trigger a very long-term switch to chronic respiratory disease. This mimics what we see in children who develop lifelong asthma. Second, we developed cell and animal models of this process to explain why it would last so long. Based on new technologies, we were able to identify a subset of lung stem cells that become reprogrammed by inhaled insults such as viral infection, sometimes in combination with other inhaled toxins like smoke or allergen. After this change in behavior, these stem cells, that are ordinarily charged with lung repair, can instead overgrow their normal boundaries and cause problems that interfere with lung function. Because these stem cells are designed to be renewable, once they are reprogrammed, they can give rise to daughter cells and thereby maintain the susceptibility to lung disease for many years, perhaps a lifetime. This paradigm applies to infections due to SARS-CoV-2, influenza virus, and any other viruses that might cause severe illness in children or adults. Thus, most recently, we see that this stem cell pathway to disease is routinely activated in patients dying of COVID-19. Correcting this altered cell behavior is therefore key to preventing this type of disease. 2. How c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210281
Entities
People
- Michael J Holtzman
Organizations
- United States Army
- Washington University in St. Louis