Using Precision Medicine to Treat Severe Asthma

By method of a randomized, placebo-controlled clinical trial, Boston Children’s Hospital will use precision medicine to treat a form of severe asthma to which Black and Latinx children and adults are disproportionately impacted.

The four-center trial comes after a half-decade of research at Boston Children’s depicting how a mutation of the gene ILR4 causes severe and difficult to treat asthma. By using precision medicine to target the gene, scientists could find a way to counter the chronic disease.

The trial called Investigating Dupilumab's Effect in Asthma by Genotype (IDEA) is set to test the monoclonal antibody, dupilumab, in 150 patients aged 12 and older with and without the ILR4 mutation. According to previous studies, the mutation is particularly common in Black and Latinx populations.

"There are a lot of disparities in asthma severity, so in this study we hope to help inner-city disadvantaged kids who disproportionately are affected by this genotype," trial principal investigator Wanda Phipatanakul, MD, in the Division of Immunology at Boston Children's said in a press release. "The treatment we are testing should especially benefit those with that genotype."

ILR4 encodes the cellular receptor for IL-4, a cytokine that impacts inflammation. With dupilumab blocking the same receptor, researchers are looking for it to also curb inflammatory responses in asthma. The drug is currently FDA-approved for treating asthma in adults and eczema in children.

The clinical trial is an outcome of previous laboratory work by Phipatanakul and Talal Chatila, MD. The work showed that mutations in IL4R caused increased airway inflammation in asthma by creating changes to the IL-4 receptor. This led to excessive airway inflammation caused by two types of T cells, Th2 and Th1.

In 2016, the team showed that the mutated IL-4 receptor changes regulatory T cells, which usually calm immune responses, into cells like inflammatory Th17 cells. Additionally, having two copies of the IL4R mutation will increase asthma severity.

By analyzing data from Phipatanakul’s earlier study in 2018, researchers discovered that having two copies of the IL4R mutation, one from each parent, combined with exposure to toxins from the air made asthma worse. The team also matched a previous finding from Chatila’s lab that indicated increased allergic inflammation in mice with the mutation when exposed to particles from car exhaust.

"We specifically wanted to look at patients with this genotype to help those most in need and to establish a reliable biomarker for use of this drug," said Phipatanakul. "Based on our earlier work, we expect that people who have two copies of the variant will respond the most."

The trial will enroll patients at Boston Children's, Brigham and Women's Hospital in Boston, the Henry Ford Health System in Detroit, and the Atlantic Health System in New Jersey.