LA JOLLA, Calif.—A new study has identified a synthetic and not naturally occurring monosaccharide, 2,4-O-di-sulfated iduronic acid (Di-S-IdoA), as a potential means of blocking T-cell recruitment to inflammatory sites and thus attenuating asthma.
The international team of researchers from Sanford-Burnham Medical Research Institute, the Max Planck Institute of Colloids and Interfaces in Germany, the Free University of Berlin in Germany, the University of California, San Diego and Shinshu University in Japan identified a novel molecule that prevents T cells from orchestrating asthma brought on by allergens. The findings, published on May 12 in Proceedings of the National Academy of Sciences, show promise for a new potent therapeutic agent to treat asthma, a chronic disease affecting more than 25 million Americans.
“We have identified a synthetic molecule, a sulfate monosaccharide, that inhibits the signal that recruits T cells to the lungs to start an asthma attack,” says Dr. Minoru Fukuda, adjunct professor in the Tumor Microenvironment and Metastasis Program at Sanford-Burnham. “The molecule substantially lessened asthma symptoms such as inflammation, mucus production and airway constriction.”
The study, performed in mouse models for asthma research, showed that the synthetic sulfate monosaccharide blocks the interaction between chemokine CCL20—a T-cell signaling protein—and heparin sulfate, a molecule that protects and immobilizes CCL20 on epithelial cells in the lung. Blocking this interaction stalled the recruitment of the T cells that trigger inflammation. The favorable results were achieved when the novel molecule was administered intravenously as well as by inhalation.
Identification of carbohydrate sequences that determine affinity to specific chemokines is a critical step for strategies to interfere with chemokine-mediated leukocyte trafficking. The study authors first characterized the development of allergic asthma in Tie2-dependent and inducible Ext1-knockout (Tie2-Ext1iKO) mice. They then demonstrated that heparin sulfate is essential for leukocyte recruitment in the peribronchial region and bronchoalveolar lavage fluid (BALF), and is crucial for induction of airway hyperresponsiveness. The glycan microarray showed a unique affinity profile of chemokine CCL20 to substructures of heparin and heparin-like oligo/di/monosaccharides. Among them, the international team identified a synthetic and not naturally occurring monosaccharide, Di-S-IdoA, as a potential inhibitor for CCL20–heparan sulfate interaction. Mice injected with Di-S-IdoA via tail vein or nasal inhalation showed attenuated leukocyte recruitment into inflammatory sites and BALF. These results demonstrate a critical role of chemokine–heparin sulfate interaction in asthma development and Di-S-IdoA as a potential drug for asthma treatment.
Although billions of dollars are spent every year on asthma medication, asthma still accounts for a startling one-quarter of all emergency room visits in the U.S. each year, about 1.75 million ER visits. And asthma is on the rise; since 1980, asthma death rates overall have increased more than 50 percent among all genders, age and ethnic groups. The death rate for asthma sufferers under 19 years old has increased by nearly 80 percent since 1980.
“There is currently no cure for asthma, and asthma control remains elusive for many patients, so there is still a need for research to find new therapies,” says Mike Tringale, senior vice president at the Asthma and Allergy Foundation of America, a national asthma patient organization that has declared May National Asthma Awareness Month.
“Pulmonary inhalation of this new molecule may help reduce asthma symptoms by suppressing chemokine-mediated inflammatory responses,” Fukuda states. “We look forward to the further development of the molecule to treat the millions of people who suffer from this chronic disease.”
Asthma is a chronic lung disease that inflames and narrows the airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath and coughing. The effects are usually temporary, but if the episode is severe, a person may need emergency treatment to restore normal breathing.
The affliction affects people of all ages, but it most often starts during childhood. In the United States, more than 25 million people are known to have asthma, and 60 percent of cases are allergic asthma. About 5 million of these people are children. Despite the availability of treatments, asthma remains poorly controlled among many patients. People with asthma can be of any race, age or sex, and treatment costs billions of dollars each year.
Sanford-Burnham Medical Research Institute takes a collaborative approach to medical research with major programs in cancer, neurodegeneration and stem cells, diabetes and infectious, inflammatory and childhood diseases. The Institute is recognized for its National Cancer Institute-designated Cancer Center and expertise in drug discovery technologies. Sanford-Burnham is a nonprofit, independent institute that employs 1,200 scientists and staff in the San Diego area and in Lake Nona, Fla., near Orlando.
