Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B.
Pharmacological modulation of humoral immunity in a nonhuman primate model of AAV gene transfer for hemophilia B.
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DOI：
10.1038/mt.2012.84
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
High KA
中科院分区：
文献类型：
--
作者：
Mingozzi F;Chen Y;Murphy SL;Edmonson SC;Tai A;Price SD;Metzger ME;Zhou S;Wright JF;Donahue RE;Dunbar CE;High KA
乙型血友病的肝脏基因转移在最近的临床研究中显示出非常有希望的结果。然而，基于基因治疗血友病和其他遗传性疾病的潜在并发症是针对治疗性转基因的中和抗体（NAb）的发展。在腺相关病毒（AAV）介导的血友病肝脏基因转移后，对凝血因子IX （F.IX）转基因产物发生NAb的风险很小，但并非没有，因为在肝脏基因转移后的实验动物中观察到F.IX的抑制抗体的形成。因此，需要调节抗转基因NAb反应的策略。在这里，我们使用抗b细胞单克隆抗体rituximab （rtx）联合环孢素A （CsA）来根除先前静脉注射表达人F.IX的AAV8载体的恒河猴体内的抗人F.IX NAb。短时间的免疫抑制（IS）可根除抗f。IX NAb与恢复血浆fix转基因产物检测。在一只动物中，IS后抗aav6抗体也降至检测以下，允许AAV载体成功再给药，并导致血浆中F.IX转基因产物的高水平（60%或正常）。虽然动物数量很少，但本研究支持B细胞靶向治疗根除aav介导的基因转移后产生的NAb的安全性和有效性。
Liver gene transfer for hemophilia B has shown very promising results in recent clinical studies. A potential complication of gene-based treatments for hemophilia and other inherited disorders, however, is the development of neutralizing antibodies (NAb) against the therapeutic transgene. The risk of developing NAb to the coagulation factor IX (F.IX) transgene product following adeno-associated virus (AAV)-mediated hepatic gene transfer for hemophilia is small but not absent, as formation of inhibitory antibodies to F.IX is observed in experimental animals following liver gene transfer. Thus, strategies to modulate antitransgene NAb responses are needed. Here, we used the anti-B cell monoclonal antibody rituximab (rtx) in combination with cyclosporine A (CsA) to eradicate anti-human F.IX NAb in rhesus macaques previously injected intravenously with AAV8 vectors expressing human F.IX. A short course of immunosuppression (IS) resulted in eradication of anti-F.IX NAb with restoration of plasma F.IX transgene product detection. In one animal, following IS anti-AAV6 antibodies also dropped below detection, allowing for successful AAV vector readministration and resulting in high levels (60% or normal) of F.IX transgene product in plasma. Though the number of animals is small, this study supports for the safety and efficacy of B cell-targeting therapies to eradicate NAb developed following AAV-mediated gene transfer.
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