Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9
Risk and prevention of anti-factor IX formation in AAV-mediated gene transfer in the context of a large deletion of F9
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DOI：
10.1006/mthe.2001.0441
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发表时间：
2001-09-01
影响因子：
12.4
通讯作者：
High, KA
中科院分区：
文献类型：
--
作者：
Fields, PA;Arruda, VR;High, KA
目前正在早期临床试验中评估几种基因治疗方法治疗严重的X连锁出血性疾病血友病的安全性。一种策略寻求通过肌内（IM）施用腺相关病毒（AAV）载体来纠正功能性凝血因子IX（血友病B）的缺陷。任何血友病治疗的潜在严重并发症是形成针对凝血因子蛋白的抑制性抗体，这是因子IX基因（F9）无效突变背景下增加的风险。在这里，我们描述了具有大量F9缺失的血友病B小鼠，这些小鼠在IM给予表达小鼠F9的腺相关病毒载体后或重复静脉输注小鼠F9浓缩物后1至2个月内形成抑制剂。在这两种情况下，抑制剂主要是IgG1免疫球蛋白，代表Th2驱动的体液免疫应答。我们进一步证明，在基于基因的方法中的抗小鼠F9抗体形成可以通过在载体施用时的瞬时免疫调节来减少。此外，该操作导致在一些血友病B小鼠中完全不存在抗小鼠F9和功能性小鼠F9的持续表达，特别是在用免疫抑制药物环磷酰胺治疗的那些动物中。这些数据与旨在避免针对分泌的转基因产物的免疫应答的临床试验和策略的设计直接相关。
The safety of several gene therapy approaches for treatment of the severe, X-linked bleeding disorder hemophilia is currently being evaluated in early phase clinical trials. One strategy seeks to correct deficiency of functional coagulation factor IX (hemophilia B) by intramuscular (IM) administration of an adeno-associated viral (AAV) vector. A potentially serious complication of any treatment for hemophilia is formation of inhibitory antibodies against the coagulation factor protein, a risk that increases in the setting of null mutations in the factor IX gene (F9). Here, we describe hemophilia B mice with a large F9 deletion that form inhibitors within 1 to 2 months after IM administration of an AAV vector expressing mouse F9 or after repeated intravenous infusion of mouse F9 concentrate. In both cases, inhibitors are primarily IgG1 immunoglobulins representing a Th2-driven humoral immune response. We further demonstrate that anti-mouse F9 antibody formation in the gene-based approach can be reduced by transient immune modulation at the time of vector administration. Moreover, this maneuver resulted in complete absence of anti-mouse F9 and sustained expression of functional mouse F9 in some hemophilia B mice, particularly in those animals treated with the immunosuppressive drug cyclophosphamide. These data have direct relevance for design of clinical trials and strategies aimed at avoiding immune responses against a secreted transgene product.