Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered
Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered
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DOI：
10.1073/pnas.0601433103
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发表时间：
2006-08-29
影响因子：
11.1
通讯作者：
Wilson, James M.
中科院分区：
文献类型：
--
作者：
Limberis, Maria P.;Wilson, James M.
呼吸道导向基因转移已成为治疗囊性纤维化和α-1抗胰蛋白酶缺乏症这两种肺部遗传性疾病的一种有前途的方法。在此，我们描述了一种新型腺相关病毒(AAV)载体AAV2/9在小鼠鼻和肺上皮细胞中的转导效率。在基因表达高峰期，AAV2/9介导的人α-1-抗胰蛋白酶基因在血清中的表达水平约为AAV2/5的60倍。我们发现AAV2/9介导的nLacZ基因在鼻腔和肺部的转移相对稳定了9个月，这表明AAV2/9介导的人α-1-抗胰蛋白酶基因在鼻腔和肺部的转导是一种祖细胞群。最有趣的是，我们发现AAV2/9在最初暴露后1个月就可以在存在高水平血清循环中和抗体的情况下重新给予治疗，而对报告基因整体表达的影响最小，使其成为一种有希望用于人类的基因转移载体。
Airway-directed gene transfer has emerged as a promising approach for the treatment of the two genetic diseases of the lung, namely cystic fibrosis and alpha-1-antitrypsin deficiency. Herein we describe the transduction efficiency of a novel adeno-associated virus (AAV) vector, AAV2/9, across murine nasal and lung airway epithelia. At the peak of gene expression AAV2/9-mediated human alpha-1-antitrypsin gene expression in serum was approximate to 60-fold better than that of AAV2/5. We found that AAV2/9-mediated nLacZ gene transfer in nasal and lung airways was relatively stable for 9 months, suggesting that a progenitor airway cell population was transduced. Most interestingly, we show that AAV2/9 can be readministered in the presence of high levels of serum-circulating neutralizing antibodies as early as 1 month after initial exposure, with minimal effect on overall reporter gene expression, rendering it a promising gene transfer vector candidate for use in humans.