This article is the third 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. In the final article in this series, we present projects that may provide therapeutics for severe asthma, pulmonary hypertension, and sleep-disordered breathing.
Asthma is a chronic lung condition in which inflammation of the airways causes them to narrow at times, resulting in wheezing, breathing difficulties, and coughing. Asthma is a common disease, affecting at least 25 million people in the United States. Available asthma treatments provide symptom control for many patients, but there are no available treatments that prevent asthma from developing or worsening or that can cure the disease. In addition, some patients with asthma have a more severe form of disease that is not controlled by current treatments.
Treating Severe Asthma with an Antibody
Roughly 5–10 percent of individuals with asthma have severe asthma that does not respond to treatment. These individuals experience difficulty breathing almost all of the time and frequently have life-threatening asthma attacks that require hospital admissions. In studying this condition, researchers at Yale University have discovered that the protein YKL-40 is elevated in the lungs and blood of a subgroup of patients with severe asthma. Moreover, the Yale scientists have established that YKL-40 plays a role in airway inflammation and airway remodeling (structural changes in the airways). To combat the negative effects of this protein, the Yale researchers have developed and are testing monoclonal antibodies against YKL-40. Derived from cloned immune cells, these antibody proteins will bind to YKL-40, marking it for destruction by other immune cells. The researchers are also developing a diagnostic test that would measure YKL-40 levels in the blood and enable doctors to determine the proper dose of the antibodies for different patients.
In testing and refining this treatment approach, Dr. Geoffrey Chupp of Yale University and Jack Elias of Brown University School of Medicine are leading a multidisciplinary team that includes experts in translational research, genomics, drug development, and immunology. The research center is also partnering with the Connecticut biotech company AxioMx to commercialize the therapeutic it is developing. If the antibodies are ultimately approved for human use, Dr. Chupp believes that the biologic will be useful in controlling both chronic symptoms of severe asthma and life-threatening flare-ups.
Improving Bronchodilation in Severe Asthma
University of Chicago
For patients with severe asthma, existing bronchodilators have limited effectiveness in relaxing airway muscles to open narrowed airways. Scientists at the University of Chicago believe these drugs often do not work because they activate a long signaling pathway, and severe inflammation interferes with the signal being relayed all the way down the pathway to achieve its effect. To overcome this problem, these investigators are developing a new class of bronchodilator that bypasses this signaling pathway altogether, acting instead at the cellular “motor” that drives muscle contraction: myosin. Smooth muscle contracts when myosin filaments pull actin filaments, which provide shape to the cell, toward the center of the cell, thereby shortening the muscle cell’s length. The molecules this center is testing inhibit this process by preventing polymerization of myosin proteins into myosin filaments.
The center’s novel approach to re-opening constricted airways is one that required the contribution of multiple scientists from various disciplines: pulmonary researchers at the University of Chicago; toxicologists at the IIT Research Institute; cell physiologists at Harvard; pharmaceutical experts at Purdue University, the University of Minnesota, and the University of Iowa; and medicinal chemists at the NIH National Center for Advancing Translational Sciences.
In leading this team of researchers, the co-principal investigators, Julian Solway, a pulmonologist at the University of Chicago, and David McCormick, a toxicologist at the IIT Research Institute, expressed their excitement at the opportunity the NHLBI has provided through CADET II to develop new candidate drugs for patients, and they are hopeful that the drugs they are developing will represent a breakthrough treatment for those with severe asthma.
In patients with pulmonary hypertension, the pulmonary arteries, which supply blood to the lungs, undergo pathological structural changes and become narrower, impairing blood flow. As a result, the right ventricle of the heart must pump harder to get blood to the lung. This continual strain progressively damages the right ventricle, eventually causing heart failure.
Arresting Vascular Changes in Pulmonary Hypertension
Johns Hopkins University
Researchers at this center believe they have discovered a way to arrest—and potentially reverse—the harmful chain of events that occurs in patients with pulmonary hypertension. Their CADET II research is the latest step in a longstanding investigation of pulmonary hypertension funded by the NHLBI. As one of the CADET I investigators, Dr. Roger Johns and his team at Johns Hopkins discovered that two proteins, resistin and resistin-like molecule beta (RELMβ), contribute to harmful changes in the architecture of the pulmonary arteries and the hearts of patients with pulmonary hypertension. Now, the researchers are refining antibodies that would target RELMβ and resistin and promote their destruction.
The investigators believe this antibody approach to treating pulmonary hypertension will be more effective than currently available medicines for the condition. Existing medicines primarily dilate the blood vessels without preventing the ongoing structural changes to the pulmonary arteries and the heart. As a result, these drugs “only slightly prolong life and improve lifestyle a little bit but do not alter the ultimate course of the disease,” Dr. Johns explained. Antibodies against resistin and RELMβ, on the other hand, should prevent changes in pulmonary vascular structure and cardiac structure and possibly reverse them. The researchers are also optimizing a biomarker—specifically, the blood serum levels and genetic polymorphisms of resistin and RELMβ—that doctors could use to evaluate the severity of pulmonary hypertension and the response to therapy.
Sleep-Disordered Breathing (SDB)
Sleep-disordered breathing refers to a group of conditions, including sleep apnea, that involve abnormal breathing patterns during sleep. Patients with obstructive sleep apnea, for example, temporarily stop breathing at various points during sleep due to a collapsed or blocked airway. The most common treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), in which patients wear a mask that gently blows air into the throat, thereby keeping the airway open. However, for a substantial portion of patients with sleep apnea, CPAP is not effective or well tolerated.
Developing an Alternative Treatment for SDB
University of Chicago
Researchers at the University of Chicago are developing new drugs for the treatment of SDB. The researchers are focusing on the carotid bodies, specific regions in the carotid arteries in the neck that sense oxygen levels in the blood and send a signal to the brain when oxygen levels become low; the brain then stimulates breathing. In patients with sleep apnea, frequent cessations in breathing cause continual stimulation of the carotid bodies, which then become hypersensitive. Increasing the sensitivity of the carotid bodies leads to further disturbances in breathing patterns.
Led by principal investigator Dr. Nanduri Prabhakar at the University of Chicago, researchers have identified a compound that reduces sensitization of the carotid bodies and restores normal breathing in animal models of sleep-disordered breathing. In their CADET II research, the investigators are now taking steps to improve the efficacy and safety of the drug candidate. Dr. Prabhakar hopes that the research will result in a drug that can treat not only SDB but also the complications that can arise from SDB, including hypertension, diabetes, and strokes.
In reflecting on these projects, Dr. Michelle Freemer, M.D., a program officer in the NHLBI Division of Lung Diseases, indicated how exciting it is to work with investigators who are translating their scientific laboratory findings into products that may help patients with lung disease and sleep-disordered breathing.