Gene therapy for severe hemophilia A employs an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in 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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Review Article|
June 6, 2024
Optimizing Liver Health Before and After Gene Therapy for Hemophilia A
Margaret V. Ragni,
University of Pittsburgh, Pittsburgh, Pennsylvania, United States
* Corresponding Author; email: ragni.bloodadvances@hematology.org
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Henry Mead,
Henry Mead
BioMarin Pharmaceutical, Inc., San Rafael, California, United States
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Ype P de Jong,
Ype P de Jong
Weill Cornell Medicine, New York, New York, United States
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Radoslaw Kaczmarek,
Radoslaw Kaczmarek
Indiana University School of Medicine, Indianapolis, Indiana, United States
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Andrew D Leavitt,
Andrew D Leavitt
University of California San Francisco, San Francisco, California, United States
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Brian Long,
Brian Long
BioMarin Pharmaceutical, Inc., San Rafael, California, United States
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Diane Nugent,
Diane Nugent
Center for Inherited Blood Disorders and CHOC Childrens Hospital, Orange, California, United States
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Denise E. Sabatino,
Denise E. Sabatino
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Sylvia Fong,
Sylvia Fong
BioMarin Pharmaceutical Inc., Novato, California, United States
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Annette von Drygalski, M.D.,
Annette von Drygalski, M.D.
University of California San Diego, San Diego, California, United States
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Christopher e Walsh,
Christopher e Walsh
Mount Sinai School of Medicine, New York, New York, United States
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Bruce Luxon
Bruce Luxon
Georgetown, Washington, District of Columbia, United States
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Blood Adv bloodadvances.2024013059.
Article history
Submitted:
February 29, 2024
Revision Received:
May 7, 2024
Accepted:
May 27, 2024
Citation
Margaret V. Ragni, Henry Mead, Ype P de Jong, Radoslaw Kaczmarek, Andrew D Leavitt, Brian Long, Diane Nugent, Denise E. Sabatino, Sylvia Fong, Annette von Drygalski, Christopher e Walsh, Bruce Luxon; Optimizing Liver Health Before and After Gene Therapy for Hemophilia A. Blood Adv 2024; bloodadvances.2024013059. doi: https://doi.org/10.1182/bloodadvances.2024013059
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