My Life, Our Future Research Repository — a rare disorder gets a rare opportunity

Researcher: Thomas Howard, MD, PhD, University of Texas Rio Grande Valley School of Medicine

Project Description: Bleeding in hemophilia A (HA)—due to plasma factor (F)VIII deficiency—is arrested and prevented by infusing therapeutic FVIII proteins (tFVIIIs). But, tFVIIIs induce neutralizing-antibodies called “FVIII inhibitors” (FEIs) in ~20% of all HA patients (HAPs). These “FEI-patients” experience greater mortality/morbidity as bleeding can only be arrested/prevented with less safe/less effective therapeutics, which are also extremely expensive. Towards developing precision-diagnostics that accurately predict patient-specific FEI-formation, we will apply powerful new systems-biologic and trans-omic methodologies to a MLOF cohort of ~1,300 severe HAPs, and will analyze the data from these omic domains using a pedigree-based generalized linear mixed-model approach implemented in the statistical genetics package SOLAR, which was developed by our team.

Researcher: Shannon Meeks, MD, Emory University and Children's Healthcare of Atlanta

Project Description: Patients with hemophilia experience differing bleeding phenotypes that persist despite controlling for residual factor activity. Genetic alterations outside of F8/F9 may account for some of this phenotypic heterogeneity. Factor V (FV) and tissue factor pathway inhibitor (TFPI) are major determinates of thrombin generation in hemophilia, and thus genetic alterations that impact plasma levels of FV, FV-short, and TFPI may modulate bleeding in these patients. We aim to investigate the prevalence of F5 variants in patients with hemophilia and determine the impact of these variants on plasma FV, FV-short, thrombin generation, and TFPI levels as well as on clinical bleeding phenotype.

Researcher: Amanda B. Payne, PhD, MPH, Centers for Disease Control and Prevention

Project Description: Inhibitors are the most important treatment-related complication among persons with hemophilia A (PWH). However, to date, inhibitor risk prediction models have been either of limited in usefulness among untreated PWH or not validated among large numbers of PWH. This project aims to evaluate the performance of inhibitor risk prediction models, that rely on genetic information, among PWH enrolled in the MLOF Research Repository by examining receiver operating characteristics curve metrics. Understanding who may be at highest risk of inhibitor development could help guide treatment decisions, particularly the use of factor versus non-factor products.

Researcher: Johnson Liu, MD, Maine Medical Center

Project Description: Variability in bleeding is well described in hemophilia, but the potential mitigating role of prothrombotic gene variants is unclear. Prior suggestive research was hampered by small sample sizes, but we propose using the MLOF Research Repository, the world’s largest repository of data including whole genome sequencing from hemophilia patients. We hypothesize that co-inheritance of prothrombotic gene variants modulates bleeding severity in patients with a defined genotype. Our specific aims: (1) We will test a panel of prothrombotic gene variants in modulating bleeding phenotype; (2) We will evaluate the role of Von Willebrand Factor gene variants in modulating bleeding phenotype.

Researchers: Zuben Sauna, PhD and Hong Yang, PhD, Center for Biologics Evaluation and Research, Food & Drug Administration, Department of Health and Human Services

Project Description: About 30% of hemophilia A patients treated with Factor VIII develop anti‐drug‐antibodies. We are trying to understand why some patients develop anti‐drug‐antibodies while others do not. We will use the information obtained from the My Life, Our Future and the American Thrombosis and Hemostasis Network to develop a comprehensive mathematical model for immune responses to therapeutic proteins. Such a model, once validated, can be used while evaluating new FVIII‐drugs to project the immunogenicity‐risk in the larger population once drugs are marketed or to plan the appropriate treatment for newly diagnosed patients. Eventually it may spur the development of specific products for different classes of hemophilia A patients.

Researcher: Ming Lim, MBBCH, MS, University of Utah

Project Description: Using the MLOF Research Repository and the ATHNdataset as a source population for non-severe hemophilia A patients, this study will attempt to determine the association between inhibitor development and F8 mutation in non-severe hemophilia A patients. Prior studies in Europe have demonstrated the potential of F8 genotyping to estimate individualized risks of inhibitor formation for those mutations with sufficient data. Specific US data on risk of inhibitor formation has immediate clinical relevance as it can help contribute to decision-making on the management of elective procedures in NSHA patients.

Researcher: Steven Pipe, MD, University of Michigan

Project Description: Patients with severe hemophilia A, factor VIII (FVIII) deficiency, exhibit variability in FVIII half-life, creating a risk for bleeding and susceptibility to progressive joint disease. These variabilities can have a profound effect on the amount of factor they use and their clinical outcomes, yet little is known about the factors that determine this variability. The ATHN/MLOF clinical database and biorepository will allow us to investigate the genetic basis for these marked inter-individual variations through analysis of a patient’s entire genetic sequence. This may in turn inform bioengineering strategies to extend the half-life of FVIII therapeutics and perhaps highlight ethnic variability and inhibitor risk.

Researcher: Kathleen Pratt, PhD, Uniformed Services University

Project Description: Both the hemophilia-causing FVIII mutation and a family history of inhibitors contribute to inhibitor risk, strongly indicating that still-unidentified genetic factors contribute to this risk. We propose to utilize the MLOF database to analyze specific immune-response-associated DNA regions to find genetic variations that contribute to inhibitor risk. Patients with lower-level immune responses to FVIII, including non-inhibitory anti-FVIII antibodies, are considered to have “partial immune tolerance” to FVIII. We wish to determine what causes some patients to develop high-titer responses while other antibody responses remain clinically insignificant. Our goal is to discover novel therapeutic targets to lower inhibitor incidences.

Researcher: Rodney Camire, PhD, Children’s Hospital of Philadelphia

Project Description: Following injury, the body rapidly responds to stop bleeding. This process involves cells in the blood and proteins (coagulation factors) that work to form a blood clot. For some people, these factors are reduced/missing and they have an increased risk of bleeding, a disorder called hemophilia A or B. Often the severity of bleeding among hemophilia patients with the same factor levels is variable. The goal of our study is to measure a protein in blood (TFPI) that works to prevent too much blood clotting and determine if changes in its levels modify the bleeding patterns in severe hemophilia.

Researcher: Jill Johnsen, MD, Bloodworks Northwest Research Institute

Project Description: Female carriers of hemophilia have excessive bleeding that is not well explained by their clotting factor levels. We propose to study carriers and male relatives in My Life, Our Future. We will study specific DNA changes for effects on gene expression that can be missed by routine testing and determine if those changes are associated with bleeding. We will also study if low levels of another blood clotting protein, von Willebrand factor, are associated with bleeding in carriers. We hope these studies will help us care for at-risk female carriers in the future.

Researcher: Tim Harris, PhD, DSc, Bioverativ Therapeutics

Project Description: Development of inhibitors remains a major complication of replacement therapy in hemophilia. While factor mutation type may largely contribute to the risk of inhibitor development, the underlying basis for why some patients develop inhibitors, while others do not, remains poorly understood. We aim to conduct an analysis of gene burden using data (genetic and medical) from My Life, Our Future to elucidate which genes play a role in inhibitor development. This includes investigation of Fc receptor variants, which have been reported to impact the immune response to FVIII. Further correlation of findings may involve characterization of antibodies using research repository samples.