Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism.
Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism.
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腺相关病毒5衣壳定向进化实现特异性肝向性
DOI：
10.1016/j.omtn.2022.03.017
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发表时间：
2022-06-14
期刊：
影响因子：
--
通讯作者：
Xiao, Xiao
中科院分区：
文献类型：
--
作者：
Wang, Yuqiu;Yang, Chen;Hu, Hanyang;Chen, Chen;Yan, Mengdi;Ling, Feixiang;Wang, Kathy Cheng;Wang, Xintao;Deng, Zhe;Zhou, Xinyue;Zhang, Feixu;Lin, Sen;Du, Zengmin;Zhao, Kai;Xiao, Xiao
治疗血友病的临床试验取得了令人瞩目的成就，为基因治疗的发展树立了里程碑。它强调了 AAV 介导的基因传递至肝脏的重要性。 AAV5 是一种独特的血清型，具有低中和抗体流行率的特点。但其肝脏感染力较弱。因此，开发具有强肝向性的新型 AAV5 衣壳突变体至关重要。为此，我们在小鼠中进行了 AAV5-NNK 文库和条形码筛选，从中我们鉴定了一种衣壳变体，称为 AAVzk2。与野生型血清型相比，AAVzk2 显示出相似的产量，但翻译后修饰位点不同。静脉注射AAVzk2的小鼠表现出比AAV5更强的肝脏转导，大致与AAV8和AAV9相当，而对其他组织或器官（例如心脏、肺、脾、肾、脑和骨骼肌）的转导无法检测到，表明其具有肝脏特异性向性。进一步的研究表明，AAVzk2 对 AAV5、AAV8 和 AAV9 的人肝细胞转导具有优越性，而 AAVzk2 的血清反应性与 AAV5 一样低。总体而言，我们提供了一种新型 AAV 血清型，有助于将强大且特异性的肝脏基因传递给大量人群，特别是那些无法通过 AAV8 和 AAV9 治疗的人群。在这项研究中，王等人。在小鼠中进行 AAV 衣壳库筛选，并鉴定出衣壳变体 AAVzk2，它特异性转导小鼠肝脏而不是其他组织或器官。此外，AAVzk2 的血清反应性与 AAV5 一样低，这表明它在大量人群中具有广阔的应用前景。
Impressive achievements in clinical trials to treat hemophilia establish a milestone in the development of gene therapy. It highlights the significance of AAV-mediated gene delivery to liver. AAV5 is a unique serotype featured by low neutralizing antibody prevalence. Nevertheless, its liver infectivity is relatively weak. Consequently, it is vital to exploit novel AAV5 capsid mutants with robust liver tropism. To this aim, we performed AAV5-NNK library and barcode screening in mice, from which we identified one capsid variant, called AAVzk2. AAVzk2 displayed a similar yield but divergent post-translational modification sites compared with wild-type serotypes. Mice intravenously injected with AAVzk2 demonstrated a stronger liver transduction than AAV5, roughly comparable with AAV8 and AAV9, with undetectable transduction of other tissues or organs such as heart, lung, spleen, kidney, brain, and skeletal muscle, indicating a liver-specific tropism. Further studies showed a superior human hepatocellular transduction of AAVzk2 to AAV5, AAV8 and AAV9, whereas the seroreactivity of AAVzk2 was as low as AAV5. Overall, we provide a novel AAV serotype that facilitates a robust and specific liver gene delivery to a large population, especially those unable to be treated by AAV8 and AAV9. In this study, Wang et al. performed AAV capsid library screening in mice and identified a capsid variant, AAVzk2, which specifically transduces murine liver rather than other tissues or organs. Moreover, the seroreactivity of AAVzk2 was as low as AAV5, implicating its promising usage in a large population.
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影响因子：
3.9
作者：
Hida, Kaoru;Won, Sang Y.;Di Pasquale, Giovanni;Hanes, Justin;Chiorini, John A.;Ostermeier, Marc
通讯作者：
Ostermeier, Marc
影响因子：
5.1
作者：
Dalkara, D.;Byrne, L. C.;Flannery, J. G.
通讯作者：
Flannery, J. G.
影响因子：
5.4
作者：
Govindasamy, Lakshmanan;DiMattia, Michael A.;Agbandje-McKenna, Mavis
通讯作者：
Agbandje-McKenna, Mavis
影响因子：
12.4
作者：
Giles, April R.;Sims, Joshua J.;Wilson, James M.
通讯作者：
Wilson, James M.
影响因子：
5.4
作者：
Bantel-Schaal, U;Delius, H;zur Hausen, H
通讯作者：
zur Hausen, H