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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.

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GENE THERAPY

Effects of transient immunosuppression on adenoassociated, 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, Federico Mingozzi, Katherine A. High, and Glenn F. Pierce

From Avigen Inc, Alameda, CA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA; and Howard Hughes Medical Institute, Children's Hospital of Philadelphia, Philadelphia, PA.

In a clinical study of recombinant adeno-associated virus-2 expressing human factor IX (AAV2-FIX), we detected 2 impediments to long-term gene transfer. First, preexisting anti-AAV neutralizing antibodies (NABs) prevent vector from reaching the target tissue, and second, CD8+ T-cell responses to hepatocyte-cell surface displayed AAV-capsid–terminated FIX expression after several weeks. Because 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 coad-ministration 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) preexisting anti-AAV8 NABs, (2) a standard T-cell immunosuppressive regimen, and (3) efficacy and safety of AAV8-FIX. We found that low titers (1:5) of preexisting NABs abrogate transduction, whereas animals with undetectable NABs are safely and effectively transduced by AAV8-FIX. Coadministration 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 patients with hemophilia B.


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