Novel Drug Treats Allergic Asthma Without Inhibiting Flu Defenses

Halting the action from calcium signals in immune cells was found to suppress the most common form of asthma without inhibiting the body’s defenses against influenza, according to a study published online in Science Advances.¹

Investigators from the NYU Grossman School of Medicine found that removing the gene for the calcium release-activated calcium (CRAC) channel comprised of ORAI1 proteins significantly decreased asthmatic inflammation in the lungs of mice associated with house dust mite feces, which is a frequent cause of allergic asthma. The study found a similar impact from blocking signals through the CRAC channel with an investigational CRAC channel inhibitor.

“Systemic application of a CRAC channel blocker suppressed allergic airway inflammation without compromising immunity to IAV infection, suggesting that inhibition of (store-operated Ca2+ entry [SOCE]) is a potential treatment for allergic airway disease,” the study authors wrote.

The researchers used charged particles—primarily calcium—from human cells to send signals and activate biological switches. The found that triggering T cells via viral proteins or allergens open channels in the outer membranes.

This action allows calcium to enter and turn on signaling pathways that control cell division and secretion of cytokine molecules that help T cells to communicate with other immune cells, according to the investigators. They noted that prior studies show CRAC channels in T cells regulate the ability to multiply into armies of cells that fight infections caused by viruses and other pathogens.

The current study found that the novel CRAC channel inhibitor decreased allergic asthma and mucus build-up in mice without having a negative impact on the ability of the immune system to fight the flu. This was the primary concern of the investigators in attempting to tailor immune-suppressing drugs for several uses.

“Our study provides evidence that a new class of drugs that target CRAC channels can be used safely to counter allergic asthma without creating vulnerability to infections,”senior study author Stefan Feske, MD, Jeffrey Bergstein professor of Medicine in the Department of Pathology at NYU Langone Health, said in a press release.² “Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure.”

Among 25 million Americans with asthma, most have asthma related to inhaled allergens, according to the study authors. They noted that allergic asthma involves increased type 2 (T2) inflammation with T helper (Th) 2 cells, which produce cytokines that are vital in normal immune defenses and disease-causing inflammation. In patients with allergic asthma, cytokines lead to the production of the IgE antibody and the recruitment of eosinophils to the lungs, which are hallmarks of the disease, according to the study.

The investigators found that genetic deletion of ORAI1 in T cells with the CRAC channel inhibitor CM4620 was able to thoroughly suppress Th2-driven airway inflammation associated with dust mite allergens. The novel drug is currently in phase 2 clinical trials for COVID-19-associated pulmonary inflammation and acute pancreatitis.

They found that CM4620 was able to significantly decrease airway inflammation vs an inactive control substance. Mice administered the drug showed much lower levels of Th2 cytokines and related gene expression. By stopping calcium from entering via CRAC channels, T cells are unable to transform in Th2 cells to produce cytokines that cause allergic asthma, according to the study.

Further, using CM4620 to inhibit CRAC channel function in T cells did not affect T cell-driven antiviral immunity, with lung inflammation and immune responses found similar in mice with and without ORAI1.

“Our work demonstrates that Th2 cell-mediated airway inflammation is more dependent on CRAC channels than T cell-mediated antiviral immunity in the lung,” study co-first author Yin-Hu Wang, PhD, said in the release.² “This suggests CRAC channel inhibition as a promising, potential future treatment approach for allergic airway disease.”

References

1. Wang, Y. H., Noyer, L., Kahlfuss, S., Raphael, D., Tao, A. Y., Kaufmann, U., Zhu, J., Mitchell Flack, M., Sidhu, I., Zhou, F., Vaeth, M., Thomas, P. G., Saunders, S. P., Stauderman, K., Curotto de Lafaille, M. A., & Feske, S. (2022, October 7). Distinct roles of ORAI1 in T cell–mediated allergic airway inflammation and immunity to influenza A virus infection. Science Advances, 8(40). https://doi.org/10.1126/sciadv.abn6552.

2. Experimental treatment approach counters allergic asthma without weakening flu defenses. NYU Grossman School of Medicine. News release. October 7, 2022. https://www.eurekalert.org/news-releases/967127