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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3321-3328.
Prepublished online as a Blood First Edition Paper on July 25, 2006; DOI 10.1182/blood-2006-04-017913.
 Previous Article | Next Article 
Submitted April 18, 2006
Accepted July 7, 2006
Effects of transient immunosuppression on adeno associated virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy
Haiyan Jiang*, Linda B. Couto, Susannah Patarroyo-White, Tongyao Liu, Dea Nagy, Joseph A. Vargas, Shangzhen Zhou, Ciaran D. Scallan, Jurg Sommer, Sharmila Vijay, Darren Warren, Federico Mingozzi, Katherine A. High, and Glenn F. Pierce
Bayer HealthCare, LLC
Benitec, Inc.
Avigen, Inc.
BayerHealth Care, LLC
Howard Hughes Medical Institute,The Children's Hospital of Philadelphia
Bayer HealthCare LLC
Charles River Laboratories
Howard Hughes Medical Institute, The Children's Hospital of Philadelphia
Bayer Healthcare, LLC
* Corresponding author; email: haiyan.jiang.b{at}bayer.com.
In a clinical study of recombinant adeno-associated virus-2 expressing human Factor IX (AAV2-FIX), we detected two impediments to long-term gene transfer. First, pre-existing anti-AAV neutralizing antibodies (NAB) prevent vector from reaching the target tissue; second, CD8+ T-cell responses to hepatocyte cell surface-displayed AAV capsid terminated FIX expression after several weeks. Since the vector is incapable of synthesizing viral proteins, a short course of immunosuppression, until AAV capsid is cleared from the transduced cells, may mitigate the host T-cell response, allowing long-term expression of FIX. To evaluate co-administration of immunosuppression, we studied AAV8 vector infusion in rhesus macaques, natural hosts for AAV8. We administered AAV8-FIX in 16 macaques via the hepatic artery and assessed the effects of [1] pre-existing anti-AAV8 neutralizing antibodies (NAB), [2] a standard immunosuppressive (IS) regimen, and [3] efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NAB abrogate transduction, whereas animals with undetectable NAB are safely and effectively transduced by AAV8-FIX. Co-administration of mycophenolate mofetil and tacrolimus with vector does not induce toxicity and does not impair AAV transduction or FIX synthesis. These findings enable a clinical study to assess the effects of immunomodulation on long-term FIX expression in hemophilia B patients.
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