文献类型：期刊文献

英文题名：Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism

作者：Wang, Yuqiu[1];Yang, Chen[2];Hu, Hanyang[1];Chen, Chen[1,2];Yan, Mengdi[1];Ling, Feixiang[1];Wang, Kathy Cheng[3];Wang, Xintao[1];Deng, Zhe[1];Zhou, Xinyue[1];Zhang, Feixu[1];Lin, Sen[4];Du, Zengmin[1];Zhao, Kai[1,2];Xiao, Xiao[1,2]

机构：[1]East China Univ Sci & Technol, Sch Bioengn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[3]NYU, Dept Biol, 24 Waverly Pl, New York, NY 10003 USA;[4]Army Med Univ, Daping Hosp, Army Med Ctr PLA, Dept Ophthalmol, Chongqing 400042, Peoples R China

年份：2022

卷号：28

起止页码：293

外文期刊名：MOLECULAR THERAPY NUCLEIC ACIDS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000788856500013)】；

基金：We greatly appreciate Dr. Wanxiang Jiang (Greentech Bioscience) for generous advice on and help with non-human primate experiments; Dr. Hu Zhou, Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, for mass spectrum analysis; and Dr. Lei Zhang, Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences & Pekin Union Medical College, for providing hemophilia B patient sera samples. This study was supported by the National Natural Science Foundation of China (grant no. 31901052), the Basic Research and Scientific Frontier Foundation of Chongqing (cstc2019jcyj-msxmX0010), and Shanghai Municipal Science and Technology Major Project.

语种：英文

摘要：Impressive achievements in clinical trials to treat hemophilia establish a milestone in the development of gene therapy. 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 rela-tively weak. Consequently, it is vital to exploit novel AAV5 capsid mutants with robust liver tropism. To this aim, we per formed 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-transla-tional modification sites compared with wild-type serotypes. Mice intravenously injected with AAVzk2 demonstrated 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 seroreac-tivity of AAVzk2 was as low as AAV5. Overall, we provide 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.