Hepatic Gene Transfer in Neonatal Mice by Adeno-Associated Virus Serotype 8 Vector
Hepatic Gene Transfer in Neonatal Mice by Adeno-Associated Virus Serotype 8 Vector
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DOI：
10.1089/hum.2011.183
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发表时间：
2012-05-01
影响因子：
4.2
通讯作者：
Wilson, James M.
中科院分区：
文献类型：
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作者：
Wang, Lili;Wang, Huan;Wilson, James M.
对于年轻时出现且后果不可逆转的遗传性疾病，早期治疗至关重要。新生儿基因治疗具有在疾病出现之前就达到治疗效果、载体需求量低、载体与细胞比例高、免疫系统相对不成熟等优点。已在多种动物模型中证明了对新生儿死亡的治疗效果或长期挽救作用。然而，新生儿阶段旺盛的细胞增殖对于非整合载体（例如腺相关病毒（AAV）载体）来说是一个重大挑战。稍微延迟注射年龄和稍后重新注射是解决此问题的两种替代策略。在这项研究中，我们通过自我互补的 AAV8 载体在新生小鼠中证明了稳健且高效的肝脏基因转移。然而，由于快速增殖引起的载体稀释，转导在几周内迅速下降。延迟注射时间改善了持续表达，尽管它也增加了对 AAV 衣壳的中和抗体 (NAb) 反应。这种方法可用于治疗进展缓慢的遗传性疾病。对于发病早、后果严重的遗传病，早期治疗至关重要。稍后第二次注射不同血清型的载体可能会克服先前存在的 NAb 并达到持续的治疗效果。
For genetic diseases that manifest at a young age with irreversible consequences, early treatment is critical and essential. Neonatal gene therapy has the advantages of achieving therapeutic effects before disease manifestation, a low vector requirement and high vector-to-cell ratio, and a relatively immature immune system. Therapeutic effects or long-term rescue of neonatal lethality have been demonstrated in several animal models. However, vigorous cell proliferation in the newborn stage is a significant challenge for nonintegrating vectors, such as adeno-associated viral (AAV) vector. Slightly delaying the injection age, and readministration at a later time, are two of the alternative strategies to solve this problem. In this study, we demonstrated robust and efficient hepatic gene transfer by self-complementary AAV8 vector in neonatal mice. However, transduction quickly decreased over a few weeks because of vector dilution caused by fast proliferation. Delaying the injection age improved sustained expression, although it also increased neutralizing antibody (NAb) responses to AAV capsid. This approach can be used to treat genetic diseases with slow progression. For genetic diseases with early onset and severe consequences, early treatment is essential. A second injection of vector of a different serotype at a later time may overcome preexisting NAb and achieve sustained therapeutic effects.