A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment?

The therapeutic landscape for people living with hemophilia A (PwHA) has changed dramatically in recent years, but many clinical challenges remain, including the development of inhibitory antibodies directed against factor VIII (FVIII) that occur in approximately 30% of people with severe hemophilia A. Emicizumab, an FVIII mimetic bispecific monoclonal antibody, provides safe and effective bleeding prophylaxis for many PwHA, but clinicians still explore therapeutic strategies that result in immunologic tolerance to FVIII to enable effective treatment with FVIII for problematic bleeding events. This immune tolerance induction (ITI) to FVIII is typically accomplished through repeated long-term exposure to FVIII using a variety of protocols. Meanwhile, gene therapy has recently emerged as a novel ITI option that provides an intrinsic, consistent source of FVIII. As gene therapy and other therapies now expand therapeutic options for PwHA, we review the persistent unmet medical needs with respect to FVIII inhibitors and effective ITI in PwHA, the immunology of FVIII tolerization, the latest research on tolerization strategies, and the role of liver-directed gene therapy to mediate FVIII ITI.
Competing Interests: Declaration of competing interests In addition to BioMarin funding for manuscript preparation, the authors report the following competing interests: L.A.V. reports no additional competing interests; M.C.O. reports grants or contracts from BioMarin, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda; consulting fees from Pfizer; payment or honoraria from BioMarin, Bayer, Novo Nordisk, Roche, and Takeda; support for attending meetings or travel from Roche and Takeda; participation in a Data Safety Monitory Board (DSMB) or advisory board with BioMarin, Bayer, Novo Nordisk, Roche, Sanofi, and Takeda; unpaid council membership with Novo Nordisk Haemophilia Foundation; and paid grants review for Grifols; R.W.H. reports grants from the National Institutes of Health, Luye Pharma, and Spark Therapeutics; royalties or licenses from Takeda; consulting fees from Regeneron and Prevail Therapeutics (Eli Lilly); payment or honoraria from BioMarin and Pfizer; ownership of US patent no. 8063022; and role as Editor-in-Chief of Molecular Therapy; N.S.K. reports consulting fees from BioMarin and CSL Behring; a leadership role with International Society on Thrombosis and Haemostasis; and service as chair of the grants review panel for Novo Nordisk; A.M.P. reports consulting fees from BioMarin; M.V.R. reports grants or contracts from BioMarin, Sanofi, Spark, Takeda, and the National Heart, Lung, and Blood Institute; payment or honoraria from BioMarin, Hemab, Takeda, and the Institute for Economic Review; a leadership role with the Foundation for Women and Girls with Bleeding Disorders; and receipt of study drug from Takeda; B.J.S.-J. reports grants or contracts from Pfizer and Spark; royalties or licenses from Cabaletta; consulting fees from Genentech and Bayer; payment or honoraria from Pfizer; participation in a DSMB or advisory board with GeneVentiv and Amarna; and stock or stock options from GeneVentiv and Amarna; D.L. reports grants or contracts from Bayer, CSL Behring, Sanofi, and Takeda; consulting fees from BioMarin, CSL Behring, Sanofi, and Takeda; and participation in a DSMB or advisory board with Spark.
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