Scientists find potential new therapy for hard-to-treat pediatric asthma patients

Between 40 and 70 percent of childhood asthma patients don’t respond well to common treatment, but because doctors believe a variety of factors— from the environment to genetics— affect the condition, identifying those who are resistant before an attack occurs has proven challenging. But now, researchers at Cincinnati Children’s Hospital have discovered a specific genetic variance that may help predict whether a patient will respond to corticosteroids, the mainstay treatment for asthma attacks.

“We really wanted to get a sense of, ‘Is there a biomarker we could use to identify patients that respond and don’t respond [to treatment], and could that pathway give us some information as to what type of treatments could those patients respond to?’” study author Gurjit Khurana Hershey, director of asthma research at Cincinnati Children’s, told FoxNews.com.

Study authors analyzed 57 children between ages 5 and 18 who were hospitalized for asthma through the emergency department at Cincinnati Children’s. When the children were admitted to the ER, researchers took an upper airway tissue sample. Researchers took the nasal  tissue sample instead of harder-to-obtain lung tissue to test participants' genetic markers.

Eighteen to 24 hours after administering the corticosteroids, an inhaled treatment, researchers again took upper airway tissue samples. They then analyzed which genes changed in the children from before to after treatment, and whether the children responded to the treatment.

In the United States, about 75 percent of children admitted to the hospital for an asthma attack will respond to corticosteroid treatment and be discharged quickly, while 25 percent won’t and will have only supportive care with oxygen supplementation at their disposal, Hershey said.

In the study, researchers pinpointed 31 genes that behaved differently among the good and bad responder groups, and of those, only five had what researchers considered high-quality prediction accuracy. All of those genes changed in the good responder group but not in the bad responder group.

In a separate group of 25 asthmatic children admitted to the ER, researchers checked those five genes before and after steroid treatment, and found that in the good responder group, those five genes had high methylation rates— meaning they were turned on— at a specific site where genes express, while in the poor responder group, they had low methylation rates at this site.

Study authors pinpointed a single gene that was consistently different between the good and bad responder groups, a finding that hinted as to why the non-responsive group wasn’t affected by the corticosteroid treatment. That gene was VNN-1, whose pathway is characteristic of additional inflammatory diseases besides asthma, including inflammatory bowel disease and system lupus erythematosus.

To check their results, researchers conducted the study in mice with asthma, and knocked out their VNN-1 before administering the steroid treatment. Sure enough, the mice whose VNN-1 pathway was knocked out, disabling methylation, did not respond to the medication.

“Because of this mouse data, we found [the VNN-1 pathway] is not just a marker but has a causative role,” Hershey said.

Drugs already approved by the Food and Drug Administration (FDA) target the VNN-1 pathway, including one for kidney disease, so researchers say repurposing them may provide a therapy for hard-to-treat childhood asthma patients in the future. Hershey’s team is now analyzing how those drugs affect mice with asthma.

The VNN-1 pathway also is involved in the synthesis of vitamin B. Humans aren’t known to be vitamin B deficient, as diets typically are rich in the nutrient, but knocking out the VNN-1 pathway in mice causes a deficiency in other compounds synthesized in this area. In the researchers’ current animal study, they are testing how supplementing the mice with those compounds may affect how they respond to corticosteroid treatment for asthma.

Asthma affects nearly 26 million people in the U.S., including close to 7 million children, according to the Centers for Disease Control and Prevention (CDC). Hershey said difficult-to-treat patients account for more than 50 percent of health care costs associated with asthma.

“If we can identify these kids, and then we can improve their response to steroids or treat them with something else— all of these would be of tremendous advantage to the patient, their family, the health care system and public health,” Hershey said.

The study’s findings were published Tuesday in the Journal of Allergy and Clinical Immunology.