Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy
Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy
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DOI：
10.1182/blood-2006-04-017913
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Pierce, Glenn F.
中科院分区：
文献类型：
--
作者：
Jiang, Haiyan;Couto, Linda B.;Pierce, Glenn F.
在一项表达人因子IX的重组腺相关病毒2（AAV 2-FIX）的临床研究中，我们检测到2种长期基因转移的障碍。首先，预先存在的抗AAV中和抗体（NAB）阻止载体到达靶组织，其次，几周后，CD 8（+）T细胞对肝细胞表面的应答显示AAV衣壳终止的FIX表达。由于载体不能合成病毒蛋白，因此在AAV衣壳从转导细胞中清除之前的短期免疫抑制过程可以减轻宿主T细胞应答，从而允许FIX的长期表达。为了评估免疫抑制的共同施用，我们研究了AAV 8载体输注恒河猴（AAV 8的天然宿主）。我们通过肝动脉在16只猕猴中施用AAV 8-FIX，并评估了（1）预先存在的抗AAV 8 NAB、（2）标准T细胞免疫抑制方案和（3）AAV 8-FIX的功效和安全性的作用。我们发现低滴度（1：5）的预先存在的NAB消除了转导，而具有不可检测的NAB的动物被AAV 8-FIX安全有效地转导。霉酚酸酯和他克莫司与载体共同给药不会诱导毒性，也不会损害AAV转导或FIX合成。这些结果使临床研究能够评估免疫调节对血友病B患者长期FIX表达的影响。
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 longterm expression of FIX. To evaluate coadministration 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.