This article is the first in a three-part series about the NHLBI CADET II program.
Although a variety of treatment options are available for patients with lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), some patients do not respond to existing medications or experience side effects that limit the patients’ ability to use the drugs. In addition, for rare lung diseases, there are often no therapeutic options. To address these treatment shortcomings for lung diseases and sleep-disordered breathing, the NHLBI created the Centers for Advanced Diagnostics and Experimental Therapeutics in Lung Diseases (CADET) program to stimulate the development of new drugs and diagnostics for pulmonary diseases and sleep-disordered breathing.
The first stage of CADET, which began in 2011 and concluded in 2013, funded centers to examine the pathways that lead to lung diseases and sleep disorders and to identify particular steps within those pathways that researchers could arrest or interfere with and thereby prevent disease development or progression. The second stage of CADET (known as CADET II) is now underway with 10 different research teams trying to develop new therapeutic products by providing the evidence needed to support a New Drug Application to the FDA. Below we present the work of three teams whose projects relate to COPD.
COPD is the third leading cause of death in the United States. Smoking tobacco is the most common cause of the disease, which includes both emphysema and chronic bronchitis. Emphysema results from damage to the air sacs, while in chronic bronchitis the airway is irritated and inflamed, causing longstanding coughing with phlegm production. Patients with emphysema and chronic bronchitis often experience shortness of breath.
Dampening Inflammation in COPD
University of Pittsburgh
In COPD, inflammation plays a role in both emphysema and chronic bronchitis. Although anti-inflammatory medications, such as corticosteroids, can be used to manage inflammation in patients with COPD, these medications have a limited effect, especially when patients have a flare-up. In addition, corticosteroids have side effects even with short-term use.
Hoping to create a drug that avoids these problems, researchers at the University of Pittsburgh are testing a new anti-inflammatory compound that targets FBXO3, a protein that appears to be important in promoting inflammation. The drug candidate binds to a site on FBXO3, preventing FBXO3 from triggering the release of pro-inflammatory cytokines.
Targeting Excessive Mucus Production in COPD and Respiratory Illnesses
Washington University of St. Louis
The excess mucus that accompanies most respiratory infections is also a hallmark of chronic airway diseases such as COPD and cystic fibrosis—and can have grave consequences. According to Washington University’s CADET II principal investigator, Michael Holtzman, mucus overproduction may be responsible for much of the suffering and death of patients with COPD, asthma, cystic fibrosis, and other chronic lung diseases. In addition, restoring mucus production to normal after the onset of COPD remains a challenge. Thanks to a discovery by Holtzman and his team, though, that may soon change.
The Washington University scientists discovered the importance of an enzyme, mitogen-activated protein kinase 13 (MAPK13), in stimulating excess mucus production. After characterizing the structure of MAPK13, the researchers designed a drug to bind to MAPK13 and inhibit its enzymatic activity. Tests of the drug candidate suggest the potential potency of this approach: in a culture of human airway epithelial cells, the drug inhibited mucus production substantially.
As the Washington University scientists continue to develop the drug, Holtzman predicts that the drug could treat not only COPD but any respiratory condition that involves excess mucus, including asthma, cystic fibrosis, and the common cold.
Developing an Effective Mucolytic Compound
University of North Carolina at Chapel Hill
While the Washington University team focuses on preventing mucus production, investigators at the University of North Carolina (UNC) at Chapel Hill are developing a drug to break up existing mucus. Such a mucolytic therapeutic could be used to treat COPD and other respiratory conditions in which mucus poses a threat, such as cystic fibrosis and influenza.
Dr. Richard Boucher, the principal investigator for the UNC center, explained that the center’s research holds promise for creating a highly potent mucolytic drug that lasts longer, may be safer, and smells better than existing drugs. The candidate drug they are testing works by breaking the disulfide bonds between the proteins that make up mucus. With the help of a company, Parion Sciences, the UNC team may also include a hydrating agent in their drug to help clear mucus after breaking apart the proteins in it.
“These studies are trying to address an unmet need in chronic lung diseases such as COPD by targeting pathways that may be responsible for disease progression with new drugs,” said Tony Punturieri, M.D., Ph.D., a program officer in the NHLBI Division of Lung Diseases. “Because the same pathways appear to have a role in other diseases, any drugs that result from these projects could be used in conditions such as cystic fibrosis or asthma.”