Lung cells.
Senior Investigator Tackles Severe Asthma: Searching for Novel Treatments One Trial at a Time

Dr. Stewart Levine, Senior Investigator in the NHLBI Laboratory of Asthma and Lung Inflammation, discovered his love of science and medicine in high school.  From there, he went on to study biology as an undergraduate student, where he had his first opportunity to participate in laboratory research working with a biology professor, Dr. Julian Shepherd, who was an entomologist.  Although he knew at the time that his future was in medicine, not insect biology, this was an extremely valuable experience that solidified his interest in scientific research.

After receiving his M.D. from the State University of New York at Stony Brook School of Medicine and his residency in internal medicine at St. Vincent’s Hospital and Medical Center in New York City, Dr. Levine did a fellowship in pulmonary diseases at the Memorial Sloan-Kettering Cancer Center in New York before coming to NIH in 1995.  . 

As a NIH fellow in the lab of Dr. James Shelhamer’s, Stewart Levine, became interested in asthma and lung inflammation. He said that while he had long had an interest in lung disease, it was Dr. Shelhamer’s lab that helped him to focus that interest on the role of inflammatory mediators and mucin hypersecretion in the regulation of airway inflammation. These primary areas of respiratory cell biology directly stimulated his interest in asthma, and when he became an independent investigator, he focused on pinpointing new mechanisms of disease pathogenesis in the hope they would translate into new therapeutic approaches for the treatment of severe asthma.

His career continued to develop when he said he had the privilege of being selected as a tenure-track investigator in 1998 within the NHLBI Division of Intramural Research (DIR).  It is there that he has benefitted from the mentorship provided by his branch chief, Dr. Joel Moss.  He was then promoted to Senior Investigator in 2007.  NHLBI was able to offer Dr. Levine the resources necessary to further his professional development.

Levine has “since been very fortunate to have had a career as a physician and scientist, which has allowed me both to help individuals on a personal level, as well as to pursue my love of science and potentially make discoveries that can potentially have a broader impact on health and disease.”

Dr. Levine’s Research

Because of the debilitating effects of severe asthma and the limited number of viable treatment options available, Dr. Levine and the larger asthma research community are making a concerted effort to identify new treatments that could help those living with severe asthma. 

“Asthma is a very complex disease so there are multiple different biological pathways that lead to the same clinical manifestations that a healthcare provider can recognize as asthma,” said Dr. Levine. “That makes it challenging to treat, especially for patients with severe disease.”

The ultimate goal, according to Dr. Levine, is to enable doctors to one day be able first to identify the relevant pathway that is active in a given patient, then target that specific pathway with a specific therapeutic, thereby increasing the effectiveness of the specific treatment.

He said that one of his current clinical trials may be a step toward that goal.  One of the main treatment options currently available for severe asthma is prednisone, a steroid or glucocorticoid.  However, prednisone has significant side effects—including high blood pressure, weight gain, increased incidence of infections, and weakening of bones (osteoporosis)—when used long term.  Because of the side effects, Dr. Levine said many patients try to avoid taking oral corticosteroids like prednisone.  In an attempt to identify an alternative treatment option to prednisone, Dr. Levine is conducting a double-blind, randomized, placebo-controlled, crossover study to assess the effectiveness of Actos, or pioglitazone, which is a diabetic drug and a PPAR-gamma agonist that also has anti-inflammatory properties.  Dr. Levine anticipates that if pioglitazone is found to be effective, it may be so for only certain subgroups of severe asthmatics.

Future research

Beyond his current trial with pioglitazone, Dr. Levine said he also is looking to identify other pathways—such as the role of apolipoproteins—that researchers may be able to target for the treatment of severe asthma. 

“Apolipoproteins are protein constituents of good and bad cholesterol, and one of their main functions in the body is to transport cholesterol either into cells or out of cells,” he explained. Dr. Levine and his colleagues found that apolipoproteins are also active in the lungs and for the most part serve a protective function in terms of asthma.  Dr. Levine’s laboratory has shown that apolipoproteins can bind to their receptors on cells in the lung and thereby suppress inflammation, mucous production and constriction of the airways.  He and his colleagues hope to utilize small proteins, or peptides, that mimic the function of larger apolipoproteins to treat severe asthma.  Laboratory tests have modeled that these mimetic peptides can markedly reduce the manifestations of allergic asthma. 

Dr. Levine’s colleague, NHLBI Principal Investigator Dr. Alan Remaley, M.D., Ph.D., Senior Investigator at the Lipoprotein Metabolism Section [[LINK]], developed a specific peptide that might represent a novel treatment approach and they hope to test this in a future clinical trial at the NIH Clinical Center.  This trial could lead to the development of inhaled mimetic peptides as a treatment for a broader population of severe asthmatics. 

“The benefit of this approach is that it targets a novel pathway that is totally distinct from corticosteroids,” Dr. Levine said. “It would be a brand new mechanistic approach for the treatment of asthma.”