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Review
. 2024 Oct 8;8(19):5203-5212.
doi: 10.1182/bloodadvances.2024013059.

Optimizing liver health before and after gene therapy for hemophilia A

Margaret V Ragni  1 , Henry Mead  2 , Ype P de Jong  3 , Radoslaw Kaczmarek  4 , Andrew D Leavitt  5 , Brian Long  2 , Diane J Nugent  6 , Denise E Sabatino  7 , Sylvia Fong  2 , Annette von Drygalski  8 , Christopher E Walsh  9 , Bruce A Luxon  10
Affiliations
Review

Optimizing liver health before and after gene therapy for hemophilia A

Margaret V Ragni et al. Blood Adv. .

Abstract

Gene therapy for severe hemophilia A uses an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in factor VIII (FVIII) activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy. In addition, gene therapy may induce an immune response to transduced hepatocytes, leading to liver inflammation and reduced FVIII activity. The immune response can be treated with immunosuppression, but close monitoring of liver function tests and factor levels is necessary. The long-term risk of hepatocellular carcinoma associated with gene therapy is unknown. Routine screening by imaging for hepatocellular carcinoma, preferable every 6 months, is essential in patients at high risk and recommended in all recipients of hemophilia A gene therapy. This paper describes our current understanding of the biologic underpinnings of how liver health affects hemophilia A gene therapy, and provides practical clinical guidance for assessing, monitoring, and managing liver health both before and after gene therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: M.V.R. receives research grants to her institution from BioMarin, Sanofi, Spark Therapeutics, and Takeda; and consulting fees from Be Biopharma, BioMarin, HEMAB, Sanofi, Spark Therapeutics, and Takeda. H.M. is an employee and shareholder of BioMarin. Y.P.d.J. served on scientific advisory boards for BioMarin and Pfizer; received consulting fees from Pfizer; and received research funding from Spark. R.K. serves on scientific advisory boards of BioMarin and Pfizer; and received research funding from Bayer. A.D.L. has received honoraria for participating in advisory board meetings for Pfizer, BioMarin, and CSL Behring; and has received institutional research support from Pfizer, BioMarin, and Spark Therapeutics. B.L. is an employee and shareholder of BioMarin. D.J.N. serves on advisory boards for BioMarin and Hemab. D.E.S. is a consultant for BioMarin and Poseida Therapeutics; and receives licensing royalties from Spark Therapeutics. S.F. is an employee and stockholder of BioMarin. A.v.D. has received honoraria for participating in scientific advisory board panels, consulting, and speaking engagements for BioMarin, Regeneron, Pfizer, Bioverativ/Sanofi, CSL-Behring, Novo Nordisk, Precision Medicine, Spark Therapeutics, Regeneron, Genentech, and UniQure; and is a cofounder and member of the board of directors of Hematherix LLC, a biotech company that is developing superFVa therapy for bleeding complications. C.E.W. is a medical consultant for Genentech, CSL Bering, BioMarin, Sanofi, and Novo Nordisk. B.A.L. serves on the data safety monitoring board for BioMarin, Spark Therapeutics, CSL Behring, and Pfizer.

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References

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