Hemophilia A is a rare sex chromosome-linked genetic bleeding disorder that affects approximately one in 5,000 live male births. Because it is caused by missing or abnormal factor VIII (FVIII), a clotting protein, the disease is also known as factor VIII deficiency. The frequency and intensity of bleeding episodes related to hemophilia A in males generally correlates with the severity of the deficiency of factor VIII.
The most common treatment for Hemophilia A is factor VIII replacement. While this approach helps a person with hemophilia clot, the infusion can also trigger harmful immune responses called inhibitors. This, in turn, can lead to less effective treatment, more bleeding, and poorer quality of life. Currently, both the risk factors for immune complications and the mechanisms that drive them are not completely understood. That stands to change, thanks to an NIH-funded multi-institutional research effort based at the University of Washington.
Jill Johnsen, MD is an Associate Professor of Medicine / Division of Hematology, a physician at the Washington Center for Bleeding Disorders (WACBD), and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). Johnsen is the primary contact for the study and will co-lead a team of investigators in a new initiative known as Hemophilia A Analytical Cohort Research Program (HARP). The HARP is supported by a grant from the National Heart, Lung, and Blood Institute. The first phase of the HARP award is a three-year, $6.6 million UG3 grant, with four more years planned to follow in a proposed second stage.
In the longitudinal study, the HARP researchers will trace the roots of risk for immune complications starting from the time in the womb. In total, the investigators plan to follow fifty pairs of mothers who have the gene change that leads to factor VIII deficiency and their babies who have severe hemophilia A.
Joining Johnsen in leading the HARP are Shannon Meeks, MD, a pediatric hematologist and immunology researcher at Emory University and Grier Page, PhD, a Senior Fellow and Senior Director of Statistical Genetics and Artificial Intelligence at RTI International. Together, the team will be focused on building the HARP NIH resource and advancing scientific studies in four main research areas: maternal biology, perinatal biology, the newborn, and immune system development in early life.
“Through the longitudinal study design, we have the opportunity to watch the human immune system evolve in ways that haven’t been seen before,” explains Dr. Johnsen. “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. 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.”
The data will help scientists and physicians in the future to better predict a patient’s inhibitor risk and develop an individualized treatment plan that might mitigate the immune response or point them to an alternative therapy. “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,” explains Dr. Johnsen.
In addition to revealing new insights on the conditions that give rise to FVIII inhibitors, the researchers aim to lay the groundwork for a customized approach based on each individual’s profile. “It’s a precision medicine program,” Dr. Johnsen emphasizes. “We’ll be performing single-cell sequencing to better understand the underlying processes. And we’re going to build a resource that will be available for other researchers to access and share.”
According to Dr. Johnsen, the resource will be a combined clinical dataset, a research database based on reams of -omics data gathered through genomics sequencing, and a biological repository of tissue and blood samples that will allow research teams around the world to explore FVIII mysteries for many years to come.
Looking ahead, Dr. Johnsen shares a vision of success for the project. “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. 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.”