Genzyme Corporation, Framingham, Massachusetts, USA.
Mol Ther. 2010 Nov;18(11):1983-94. doi: 10.1038/mt.2010.175. Epub 2010 Aug 24.
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 ~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.
腺相关病毒 (AAV) 载体的肝脏定向基因治疗有效地治疗了溶酶体贮积病 (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 抗体在多大程度上可以阻止普遍接触过 AAV 的灵长类动物中 AAV8 介导的肝脏转导,我们定量研究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的转基因表达的影响。使用之前临床试验中报告的最高病毒剂量,将含有相对较低抗 AAV8 滴度的 NHP 血清被动转移到小鼠中会阻止肝脏转导,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 名人类的抗 AAV8 滴度的调查,我们预测高剂量全身基因治疗将成功转导 >50%的人类患者的肝脏。然而,尽管在具有等效抗 AAV8 滴度的小鼠和猴子中给予高剂量 AAV8 会导致类似的肝脏载体拷贝数,但在灵长类动物中的转基因表达比小鼠低约 1.5 个对数级。这表明在这些物种中载体命运不同,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使用肝脏定向基因治疗方法在患者中实现 LSD 基因的临床意义上的表达水平。