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
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).
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.
Presented by Daniel Hart, BSc, MBChB, MRCP, FRCPath, PhD and Johnny Mahlangu, BSc, MBBCh, MMed, FCPath
Presented by Daniel Hart, BSc, MBChB, MRCP, FRCPath, PhD and Wolfgang A. Miesbach, MD, PhD
Presented by Daniel Hart, BSc, MBChB, MRCP, FRCPath, PhD and Declan Noone
Presented by Daniel Hart, BSc, MBChB, MRCP, FRCPath, PhD and Maria Elisa Mancuso, MD, PhD