Breaking Transgene Tolerance via Immunosuppression

Breaking Transgene Tolerance via Immunosuppression
Highlights From NHF's 16th Workshop on Novel Technologies and Gene Transfer for Hemophilia

Breaking Transgene Tolerance via Immunosuppression

Valder R. Arruda, MD, PhD
Associate Professor of Pediatrics
Perelman School of Medicine, University of Pennsylvania
Center for Cellular and Molecular Therapies (CCMT)
Children's Hospital of Philadelphia

Key Data Points

Timing of administration of ATG and immune response to the transgene

Studies in non-human primates (NHP), pretreated with mycophenolate mofetil (MMF) starting 1 week before vector administration and rapamycin starting the day of vector administration, demonstrated that administration of T-cell immunosuppression (with rabbit anti-thymocyte globulin, rATG) concomitant with AAV vector resulted in development of FIX antibodies and an increased Th17/Treg ratio (left panel) whereas administration of ATG 5 weeks after the AAV vector resulted in no FIX antibodies and a lower Th17/Treg ratio (right panel).

Summary: specific target-depletion lymphocyte and/or timing

To summarize this series of studies, immunosuppression with minimal reduction in Treg cells is optimal for ensuring liver-mediated immune tolerance to FIX transgene expression. In NHPs, pretreatment with MMF and rapamycin, followed by delayed administration of rATG was able to provide sustained immune tolerance whereas rATG or daclizumab administered at the time of vector infusion was not.


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Supported by educational grants from Bayer, BioMarin, CSL Behring, Freeline Therapeutics Limited, Pfizer Inc., Spark Therapeutics, and uniQure, Inc.

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