Drug blocks a cell receptor that is mutated disproportionately in people of color
Under a $10 million grant, a randomized, placebo-controlled clinical trial led by Boston Children’s Hospital will test a personalized treatment for a form of severe asthma to which Black and Latinx children and adults are especially vulnerable. Funded by the National Institute of Allergy and Infectious Diseases (NIAID), the four-center trial follows a half-decade of research at the hospital showing how a mutation in the gene ILR4 causes severe, hard-to-treat asthma — and the potential for an existing drug to counter it.
The trial, called Investigating Dupilumab’s Effect in Asthma by Genotype (IDEA), will test a monoclonal antibody, dupilumab (Dupixent®), in 150 patients age 12 and older with and without the ILR4 mutation. Previous studies have found this mutation to be especially 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,” says trial principal investigator Wanda Phipatanakul, MD, in the Division of Immunology at Boston Children’s. “The treatment we are testing should especially benefit those with that genotype.”
ILR4 encodes the cellular receptor for IL-4, a cytokine (chemical messenger) that plays a key role in inflammation. Duplimab blocks the same receptor, and the researchers hope it will also curb inflammatory responses in asthma. The drug is already FDA-approved for the treatment of asthma in adults and eczema in children.
Calming inflammatory responses in asthma
The clinical trial is a natural outcome of earlier laboratory work by Phipatanakul and Talal Chatila, MD, also in the Division of Immunology. They showed that mutations in IL4R drive excessive airway inflammation in asthma by causing changes in the IL-4 receptor, leading to increased airway inflammation caused by two types of T cells — Th2 and Th17. In fact, they showed in 2016 that the mutated IL-4 receptor converts regulatory T cells, which normally help calm immune responses, into cells much like inflammatory Th17 cells. Having two copies of the IL4R mutation (one from each parent) increases asthma severity accordingly.
In 2018, analyzing data from Phipatanakul’s earlier School Inner-city Asthma Study, the researchers found that having two copies of the ILR4 mutation combined with exposure to toxins in the air (based on classroom air samples) made asthma worse. This matched an earlier finding from Chatila’s lab that showed 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,” says 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. For more information, visit ClinicalTrials.gov, email [email protected], or call 857-218-5336.
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