The national blueprint for future basic and translational research to understand factor VIII immunogenicity: NHLBI State of the Science Workshop on factor VIII inhibitors.

INTRODUCTION

Inhibitor formation against coagulation factor VIII (FVIII) is an unresolved serious problem in replacement therapy for the X-linked bleeding disorder haemophilia A. Although FVIII inhibitors have been extensively studied, much of the basic mechanism of this immune response remains to be uncovered.

AIM

Within the NHLBI State of the Science Workshop on Factor VIII Inhibitors, Working Group 3 identified three scientific priorities for basic and translational research on FVIII inhibitor formation.

METHODS

A larger list of potential areas of research was initially developed as a basis for subsequent prioritization. Each scientific goal was further evaluated based on required effort, potential impact, approach, methods, technologies and models.

RESULTS

The three priorities include the following: activation signals and immune regulation that shape the response to FVIII (including innate immunity, microbiome, adaptive immunity and regulatory T cell studies in humans); utility of animal models and non-animal approaches (in silico, genetic, single-cell/sorted population "omics," in vitro) to help predict inhibitor formation and identify novel therapeutics; and impact of the source of FVIII, its structure and von Willebrand factor on immunogenicity and tolerance.

CONCLUSIONS

Early interactions between FVIII and the immune system, biomarker development and studies in different patient groups (previously treated or untreated, with or without inhibitor formation, patients undergoing immune tolerance induction or gene therapy) deserve particular emphasis. Finally, linking basic to clinical studies, development of a repository for biospecimens and opportunities for interdisciplinary research training are important components to solving the urgent problem of inhibitor formation.