Study to Trace Onset of Inhibitors in Babies With Severe Hemophilia A

NIH $6.6M grant to aid understanding of immune reaction to replacement therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The National Institutes of Health (NIH) is supporting a university’s research into the risk factors and underlying mechanisms involved in the development of neutralizing antibodies, or inhibitors, against replacement therapies in people with hemophilia A.

The $6.6 million, three-year grant from the NIH’s National Heart, Lung, and Blood Institute comes with the possibility of additional funding for a proposed four-year second phase of this study.

Led by Jill Johnsen, MD, with the University of Washington, researchers will use the funds to launch an initiative called the Hemophilia A Analytical Cohort Research Program (HARP). HARP will follow mothers and their babies with severe hemophilia A — beginning when the child is in the womb — to identify the root causes of inhibitor development.

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“We believe if we can better understand why inhibitors develop in some people but not others, we should be able to identify more effective tests and interventions for patients,” Johnsen said in a university press release. Johnsen, an associate professor of hematology at the university, is also a researcher with its Institute for Stem Cell and Regenerative Medicine, and a physician at the Washington Center for Bleeding Disorders.

Hemophilia A is caused by mutations in the F8 gene, leading to a missing or defective factor VIII (FVIII), a clotting protein in the blood. The gene resides on the X chromosome, and females inherit two copies of this gene, one from each parent. Males inherit one X chromosome from their mother, and one Y chromosome from their father.

Study into how inhibitors develop in hemophilia A patients

Women who carry a mutated copy of F8 on one X chromosome and a healthy version on the other are not likely to develop hemophilia, but they can still pass the faulty gene to their children. This is why hemophilia A is significantly more common in males — a boy who inherits an X chromosome with a mutated F8 gene from his mother will develop the disease.

Replacement therapy, which entails supplying the missing FVIII to patients, is the most common treatment for hemophilia A. However, about one-third of patients develop inhibitors against the delivered clotting factor, rendering treatment less effective.

Risk factors are for developing this immune response against replacement therapy, however, are not completely understood.

HARP will follow 50 pairs of women with a mutated F8 gene copy and their babies with severe hemophilia A, with the goal of tracing the root causes of inhibitor development.

“Through the longitudinal study design, we have the opportunity to watch the human immune system evolve in ways that haven’t been seen before,” Johnsen said.

“We’re going to study the pregnancy, follow each mother through her delivery, and then follow the mother and baby as a bonded pair for the first years of life,” she added. “We’ll be collecting blood samples and data as the babies live their lives and are treated for hemophilia, all the while tracking who makes an inhibitor that causes the body to react to the FVIII replacement treatment and who does not.”

Leading the HARP study alongside Johnsen will be Shannon Meeks, MD, a pediatric hematologist and immunology researcher at Emory University in Atlanta, and Grier Page, PhD, a senior fellow and senior director of statistical genetics and artificial intelligence at RTI International, a nonprofit based in North Carolina.

Study findings are expected to help scientists in better understanding a patient’s risk for inhibitor development, and doctors in developing individualized treatment plans to avoid unwanted immune responses to replacement therapy or in directing patients to an alternate treatment.

HARP data to be made available to researchers worldwide

But first the mechanisms underlying inhibitor development need to be studied.  The team will do this, in part, using a process called single-cell sequencing, which allows the DNA of specific, individual cell types to be analyzed for changes that might contribute to its development.

This work will also benefit the broader research community.

“We’re going to build a resource that will be available for other researchers to access and share,” Johnsen said in a separate institute press release. That resource will include clinical and genetic data, as well as blood and tissue samples collected over the course of the study, and be open to researchers worldwide.

To Johnsen, HARP’s success will be measured in two ways.

“One marker of success is building a community that’s engaged in research and that gives back and listens to what’s important to the people who live with bleeding disorders,” she said. “The second part is throwing a light on why some babies have an immune system that is generally tolerant of factor VIII, why in others the immune response goes awry, and how to get it under control. Whatever we find, basic science will lead the way.”