Effects of FVIII immunity on hepatocyte and hematopoietic stem cell-directed gene therapy of murine hemophilia A.

• Type of Material: Article
• Authors: Allison M Lytle, Emory University; Harrison C Brown, Emory University; Na Yoon Paik, Emory University; Kristopher A Knight, Emory University; J Fraser Wright, University of Pennsylvania, Philadelphia; Harold Spencer, Emory University; Christopher Doering, Emory University
• Language: English
• Date: 2016
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Official journal of the American Society of Gene & Cell Therapy. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/mtm.2015.56
• Title of Journal or Parent Work: Molecular Therapy - Methods and Clinical Development
• ISSN: 2329-0501
• Volume: 3
• Start Page: 15056
• End Page: 15056
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health/National Heart, Lung and Blood Institute (C.B.D. and H.T.S.) and Hemophilia of Georgia (C.B.D. and H.T.S.).
• Research Categories: Health Sciences, Immunology; Biology, Cell; Health Sciences, Pharmacology

Abstract

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.