Department of Biochemistry, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
Center for Gene Therapy Research, Jichi Medical University, Shimotsuke, Tochigi, Japan.
J Gene Med. 2023 Aug;25(8):e3505. doi: 10.1002/jgm.3505. Epub 2023 Apr 12.
Intravenous administration of adeno-associated virus (AAV) vectors is a promising gene therapy approach for monogenic diseases. However, re-administration of the same AAV serotype is impossible because of the induction of anti-AAV neutralizing antibodies (NAbs). Here, we examined the feasibility of re-administrating AAV vector serotypes different from the initial AAV vector serotype.
Liver-targeting AAV3B, AAV5, and AAV8 vectors were intravenously injected in C57BL/6 mice, and the emergence of NAbs and the transduction efficacy following re-administration were evaluated.
For all serotypes, re-administration of the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5, anti-AAV5 NAbs did not react with other serotypes, resulting in successful re-administration with the other serotypes. AAV5 re-administration was also successful in all mice treated with AAV3B and AAV8. Effective secondary administration of AAV3B and AAV8 was observed in most mice initially administrated AAV8 and AAV3B, respectively. However, few mice developed NAbs cross-reacting with the other serotypes, especially those with close sequence homology.
In summary, AAV vector administration induced NAbs relatively specific to the administrated serotype. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice.
腺相关病毒（AAV）载体的静脉内给药是一种有前途的单基因疾病基因治疗方法。然而，由于诱导抗 AAV 中和抗体（NAb），同一 AAV 血清型的再给药是不可能的。在这里，我们研究了给予与初始 AAV 载体血清型不同的 AAV 载体血清型的再给药的可行性。
肝靶向 AAV3B、AAV5 和 AAV8 载体被静脉内注射到 C57BL/6 小鼠中，并评估了再给药后 NAb 的出现和转导效率。
对于所有血清型，同一血清型的再给药是不可能的。尽管 AAV5 诱导的 NAb 中和活性最高，但抗 AAV5 NAb 与其他血清型不反应，导致其他血清型的再给药成功。AAV5 再给药在所有用 AAV3B 和 AAV8 治疗的小鼠中也是成功的。在最初接受 AAV8 和 AAV3B 给药的大多数小鼠中，观察到 AAV3B 和 AAV8 的有效二次给药。然而，很少有小鼠产生与其他血清型交叉反应的 NAb，尤其是那些具有密切序列同源性的 NAb。
总之，AAV 载体给药诱导的 NAb 相对特异于给药的血清型。通过在小鼠中切换 AAV 血清型，可以成功实现针对肝转导的 AAV 的二次给药。
