Systemic AAV (adeno-associated virus) gene therapy is a promising approach for the treatment of inborn errors of metabolism, but questions remain regarding its potency and durability. Tolerogenic ImmTOR nanoparticles encapsulating rapamycin have been shown to block the formation of neutralizing anti-capsid antibodies, thereby enabling vector re-administration. Here, we further demonstrate that ImmTOR admixed with AAV vectors also enhances hepatic transgene expression at the initial dose of AAV vector, independent of its effects on adaptive immunity. ImmTOR enhances AAV trafficking to the liver, resulting in increased hepatic vector copy numbers and transgene mRNA expression. Enhanced transgene expression occurs through a mechanism independent of the AAV receptor and cannot be replicated in vivo with free rapamycin or empty nanoparticles. The multipronged mechanism of ImmTOR action makes it an attractive candidate to enable more efficient transgene expression at first dose while simultaneously inhibiting adaptive responses against AAV to enable repeat dosing.

系统性 AAV（腺相关病毒）基因治疗是治疗先天性代谢错误的一种有前途的方法，但关于其效力和持久性的问题仍然存在。已显示包裹雷帕霉素的耐受性 ImmTOR 纳米颗粒可阻止中和抗衣壳抗体的形成，从而使载体重新给药成为可能。在这里，我们进一步证明，与 AAV 载体混合的 ImmTOR 在 AAV 载体的初始剂量下也增强了肝脏转基因表达，与其对适应性免疫的影响无关。ImmTOR 增强 AAV 向肝脏的运输，导致肝脏载体拷贝数和转基因 mRNA 表达增加。增强的转基因表达通过独立于 AAV 受体的机制发生，并且不能在体内用游离的雷帕霉素或空纳米颗粒复制。