Inhibiting Certain Protein in Severe Asthma Patients Could Improve Treatment
By: Lawerence Synett
The U.S. Centers for Disease Control estimates that around 25 million Americans have asthma.
Of those, around 90 to 95 percent are considered to have mild or moderate asthma, which is generally well controlled by medications, including corticosteroids. The remaining 5 to 10 percent are afflicted with what is termed “severe” or “steroid-refractory” asthma, which is controlled very poorly, if at all, by the usual medications. Individuals with this form have a very poor quality of life, and severe asthma is estimated to be responsible for about half of the $56 billion in yearly economic impact attributable to the disease overall in the U.S.
Experts from the University of Pittsburgh and UPMC previously published work demonstrating that about 50 percent of the severe asthma cases are characterized by an immune system response that is different than in milder disease and involves an inflammatory protein called interferon-gamma.
Using mice with severe asthma, researchers found that interferon-gamma was responsible for promoting airway constriction as seen in human asthma leading to difficulty breathing. New research recently published inJCI Insight aimed at blocking the immune system’s response that leads to interferon-gamma production and poor lung function.
A. In general, we are studying severe asthma because essentially no effective treatment is available. We have been working for around 8 years to identify adverse immune system responses in human severe asthma and to reproduce these responses in mice with the goal of developing novel methods of treatment. Studying the protein interferon regulatory factor 5 (IRF5) presented itself because previously published work had linked it to increased interferon-gamma production in cell culture systems. This led us to examine whether an increase in IRF5 expression levels could be detected in human subjects with severe asthma and in our mouse model that recapitulates the human disease. When this was found to be true in 50 percent of subjects, who typically also show elevated interferon-gamma levels in their airways, and was also recapitulated in the mice, the rest of the study followed.
What were the key findings/results?
A. We found that IRF5, which promotes the development of cells that make interferon-gamma, is also elevated in the lungs of humans and mice with severe asthma. In our study, mice that do not express IRF5 did not develop severe asthma, but rather only a milder form of the disease. Importantly in addition, the response to corticosteroids normally absent in severe asthma was also restored. This is important since essentially all human severe asthmatics are being treated with corticosteroids even though the therapy is not particularly effective.
What is the significance of the findings?
A. The significant findings in the mouse model of asthma are two-fold. First, the part of the immune response leading to airway constriction is blocked in the absence of IRF5. And second, under this scenario, the asthma-like features observed is a milder form of the disease, which appears to respond to conventional therapy. This suggests that a similar two-part approach combining inhibition of IRF5 with standard corticosteroids could be effective in human severe asthma where current therapy is largely ineffective.
What is your approach to the problem and what are the strengths of your approach?
A. The approach was to use our mouse model that replicates key features of human severe asthma to show that eliminating the pathway leading to interferon-gamma production greatly reduces airway constriction. The interferon-gamma production pathway was eliminated by studying mice that do not have a functional gene for IRF5 and therefore are not able to express IRF5 protein.
What are the implications of these findings?
A. The main implication is that inhibiting IRF5 could vastly improve airway function in human severe asthma where high expression of interferon-gamma is found, with the potential added benefit of restoring effectiveness of corticosteroids in controlling other aspects of the disease.
Methods for inhibiting IRF5 in humans are well under development and severe asthmatics are already being treated with corticosteroids so fairly rapid transition to clinical application is feasible.
Furthermore, inhibition of IRF5 is also being investigated by other researchers as a treatment for autoimmune disorders such as lupus. This represents an example of a general push towards so-called personalized or precision medicine, where a patient or a group of patients is treated based upon specific features of their particular disease.
The lead author in this study was Dr. Timothy Oriss, and it was conducted in collaboration with Dr. Sally Wenzel and Dr. Prabir Ray, all from the Division of Pulmonary Medicine and Pitt Asthma Institute.
The U.S. Centers for Disease Control estimates that around 25 million Americans have asthma.
What led you to pursue this research?
