Preexisting Immunity and Low Expression in Primates Highlight Translational Challenges for Liver-directed AAV8-mediated Gene Therapy
Preexisting Immunity and Low Expression in Primates Highlight Translational Challenges for Liver-directed AAV8-mediated Gene Therapy
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DOI：
10.1038/mt.2010.175
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发表时间：
2010-11-01
影响因子：
12.4
通讯作者：
Scheule, Ronald K.
中科院分区：
文献类型：
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作者：
Hurlbut, Gregory D.;Ziegler, Robin J.;Scheule, Ronald K.
使用腺相关病毒（AAV）载体的肝脏定向基因疗法有效地治疗溶酶体贮积病（LSD）的小鼠模型。我们询问这些结果是否可能转化为患者。为了了解预先存在的抗AAV8抗体在何种程度上可以阻碍通常预先暴露于AAV的灵长类动物中AAV8介导的肝脏转导，我们量化了预先存在的抗体对小鼠和非人灵长类动物（NHP）模型中肝脏转导和随后转基因表达的影响。使用先前在临床试验中报道的最高病毒剂量，将含有相对低的抗AAV8滴度的NHP血清被动转移到小鼠中阻断了肝脏转导，这可以通过将载体剂量增加十倍来部分克服。基于这一点以及对112名人类中抗AAV8滴度的调查，我们预测高剂量全身性基因治疗将在>50%的人类患者中成功地治疗肝脏。然而，尽管向小鼠和猴施用具有相等抗AAV8滴度的高剂量AAV8导致相当的肝载体拷贝数，但灵长类动物中所得的转基因表达类似于比小鼠低1.5个对数。这表明载体命运在这些物种中不同，并且仅专注于克服预先存在的载体特异性抗体的策略可能不足以在患者中使用肝脏定向基因治疗方法实现LSD基因的临床有意义的表达水平。
Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was similar to 1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.