Preclinical Development of a New Kinase Inhibitor for COPD
Abstract
Obstructive lung disease mainly in the form of chronic obstructive pulmonary disease (COPD) but also related disease in the form of asthma and asthma-COPD overlap has become the third leading cause of death in the U.S., killing over 150,000 people every year. COPD affects more than 25 million adults resulting in direct healthcare costs of $72 billion each year, while asthma affects another 26 million people and costs another $15 billion. Moreover, prediction models show no decrease in these rates in the next 20 years, with a projected epidemic of COPD hospitalizations over the next 15 years that will make COPD the most common cause of hospitalization, surpassing ischemic heart disease. These figures for the overall U.S. population are even worse for U.S. military populations. A survey of Department of Veterans Affairs (VA) medical centers show that 33%-43% of Veterans suffer from COPD, and studies of military deployed in Iraq and Afghanistan find increased rates of obstructive lung disease at earlier career stages as well. These more recent deployments have encountered additional exposures to inhaled toxins including burn pits, sand, and air pollution as well as high rates of tobacco smoke exposure and respiratory viral infection that interact together to drive the development and exacerbation of obstructive lung disease. Despite the massive impact of obstructive lung disease in personal and economic terms, there are currently no drug treatments that address the underlying cause of the disease and thereby change how the disease might develop or progress in severity with each exacerbation. Instead, current approaches represent symptomatic treatment. For asthma that has provided some improvement in respiratory symptoms, but in the case of COPD, there has been little progress at all. In general, we use drugs for COPD that were developed for asthma and do not work effectively in COPD. Similarly, the attempts at new drugs have not provided little benefit for even the symptoms of COPD let alone addressing the underlying cause of the disease. To respond to this unmet need, we will require a new understanding of how the obstructive lung disease 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 COPD 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 obstructive lung disease develops. 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 set of stem cells in the lung that become reprogrammed by inhaled insults such as viral infection, particularly in combination with other inhaled toxins like smoke. After this change in behavior, these stem cells, which are ordinarily charged with lung repair, can instead cause inflammation and mucus production that are key to the problems of obstructive lung disease. Because these stem cells are made 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. Correcting this bad cell behavior is therefore key to preventing future exacerbation and progression of obstructive lung disease. (2) How can we deliver the first disease-modifying drug for COPD for pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010603
Entities
People
- Michael J Holtzman
Organizations
- United States Army
- Washington University in St. Louis