Michael J. Holtzman, MD, director of the Division of Pulmonary & Critical Care Medicine at Washington University School of Medicine in St. Louis, has received awards totaling $7.5 million to support innovative research aimed at defining and controlling chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
The largest grant, a $6.6 million outstanding investigator award from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), recognizes physician-scientists who have a track record of highly successful and innovative research and are considered likely to make major advances in their respective fields with the support of continuous funding for seven years.
The award also recognizes that chronic respiratory disease has become the third most common cause of death in the U.S. and the fifth worldwide. Despite the devastating impact of respiratory diseases, most commonly in the form of asthma and COPD, there are still no drugs to precisely address the root causes of these disorders and provide long-lasting relief for such patients.
“Respiratory diseases are a major public health problem,” said Holtzman, the Selma and Herman Seldin Professor of Medicine. “But we still have no drug treatment to correct the most severe forms of this type of disease. In these cases, particularly COPD, all we can do is provide some degree of symptomatic relief. The disease continues to flare and progress toward increasing disability and mortality.
“In the case of asthma, we prescribe the same types of drugs today that we did 50 years ago, again with only temporary and partial improvement in symptoms,” he said. “There are new biologics marketed aggressively to control inflammation, but these agents only work about half of the time and even then only in a subset of patients. The approach also requires injections with increased costs, complications and side effects and comes with restrictions against use in children or during infections, which is often when the drug is needed most. Most of all, none of the existing treatments address the underlying abnormality that we propose is key to respiratory diseases.”
Holtzman argues for a new approach. He said his lab’s work suggests there may be a way to help patients with chronic lung disease if new drugs can target a distinct type of stem cell that becomes reprogrammed and then inappropriately drives airway inflammation and mucus production, the major drivers for clinical problems.
In healthy people, limited inflammation and mucus production act as an ancient but critical defense mechanism. But overproduction of mucus can turn deadly if left unchecked.
“Stem cells that give rise to mucus cells lining the airway and other sites are part of our immune defense strategy,” Holtzman said. “Those defenses are activated in response to inhaled troublemakers, especially common respiratory viruses, and this reaction prevents airway injury and promotes repair. Once the problem is resolved, the system should go back to a normal baseline level. But in some people, the stem cell is changed in a way that continues to promote inflammation and mucus production and ultimately compromises airway function even for normal breathing. We are identifying therapeutic targets and corresponding drugs that will dial back this stem cell response in a way that achieves a long-term correction.”
As a basis for his new grant, Holtzman and his team have identified a distinct subtype of stem cells in the lining of the airway. These cells are responsible for orchestrating the inflammation and mucus production of the respiratory system. They can switch into overdrive during disease, activating immune cells that promote inflammation and making daughter cells that respond to inflammation by turning into mucus-producing cells. Defining and controlling the mechanism that reprograms stem cells toward disease is a major goal of his new grant.
In that regard, the Holtzman group already has identified master regulators that are critical to the disease-producing behavior of lung stem cells. Through the efforts of an innovative drug discovery program launched 10 years ago, Holtzman and his colleagues also have developed new compounds that very effectively correct stem cell reprogramming and the associated inflammatory disease.
Research from his lab in animal models has shown that one of the most promising compounds, when given orally, is effective and safe for preventing airway inflammation and mucus production after a common type of respiratory viral infection. Based on these results and initial safety studies, Holtzman and his team have reached the stage of final testing and application to the Food and Drug Administration for the compound to be designated as an investigational new drug. Holtzman and his team then will be able to move forward with clinical trials in people with exacerbations of asthma, COPD and related upper airway disorders such as rhinitis and sinusitis.
In related work, the researchers also showed that similar stem cells are not just present in the airway, and decided to test their new inhibitors in other tissues and diseases. In a discovery that might seem surprising, they showed that some of their compounds were also very potent in blocking stem cell growth and invasiveness in models of breast cancer, including the most severe form, called triple-negative breast cancer, for which no specific and effective treatments are yet available.
“Your first reaction might be to wonder how in the world such similar compounds could be effective in what seem to be such different tissues,” Holtzman said. “But airway and breast tissues and other related sites share secretory function and overlap in how this function is controlled. As a result, our compounds can be precisely tailored to address whether the dysregulated stem cell is in airway versus breast tissue, or other sites as well.”
In addition to the new award to define and control stem cell behavior, Holtzman also formed a startup company to help bring the drug compounds to market. To support these efforts, he received a NIH Small Business Technology Transfer (STTR) grant for $300,000 for the compound specific to breast cancer and another STTR grant for $300,000 for a compound targeting airway disease. The research group also received a $250,000 award from the Siteman Investment Program to further support the development of the new compound for breast cancer. The strategy, he said, is to combine academic and commercial activities to finally get these new kinds of compounds into practice as quickly as possible.
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