Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood-brain barrier in rodents and primates.
Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood-brain barrier in rodents and primates.
复制标题
腺相关病毒血清型 9 的变体，在啮齿类动物和灵长类动物中具有增强的血脑屏障渗透性。
DOI：
10.1038/s41551-022-00938-7
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发表时间：
2022
影响因子：
28.1
通讯作者：
Bei,Fengfeng
中科院分区：
文献类型：
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作者：
Yao,Yizheng;Wang,Jun;Liu,Yi;Qu,Yuan;Wang,Kaikai;Zhang,Yang;Chang,Yuxin;Yang,Zhi;Wan,Jie;Liu,Junfeng;Nakashima,Hiroshi;Lawler,SeanE;Chiocca,EAntonio;Cho,Choi-Fong;Bei,Fengfeng
用于治疗中枢神经系统疾病的基因疗法的开发受到有效穿过血脑屏障（BBB）的腺相关病毒（AAV）的有限可用性的阻碍。在这里，我们报告了在病毒衣壳上展示细胞穿透肽的AAV9变体的合理设计，以及两种变体AAV.CPP.16和AAV.CPP.21的鉴定，其在全身递送时具有改善的中枢神经系统细胞的转导效率（相对于AAV9亲本载体，在4种小鼠品系中为6至249倍，在食蟹猴中为5倍）。我们还表明，AAV.CPP.16的嗜神经性在年轻和成年猕猴中得以保留，该变体相对于AAV9显示出增强的BBB转胞吞作用以及增加的细胞转导效率，并且它可用于在胶质母细胞瘤的小鼠模型中递送抗肿瘤有效载荷。能够有效穿透BBB的AAV衣壳将促进针对中枢神经系统的基因疗法的临床翻译。
The development of gene therapies for the treatment of diseases of the central nervous system has been hindered by the limited availability of adeno-associated viruses (AAVs) that efficiently traverse the blood–brain barrier (BBB). Here, we report the rational design of AAV9 variants displaying cell-penetrating peptides on the viral capsid and the identification of two variants, AAV.CPP.16 and AAV.CPP.21, with improved transduction efficiencies of cells of the central nervous system on systemic delivery (6- to 249-fold across 4 mouse strains and 5-fold in cynomolgus macaques, with respect to the AAV9 parent vector). We also show that the neurotropism of AAV.CPP.16 is retained in young and adult macaques, that this variant displays enhanced transcytosis at the BBB as well as increased efficiency of cellular transduction relative to AAV9, and that it can be used to deliver antitumour payloads in a mouse model of glioblastoma. AAV capsids that can efficiently penetrate the BBB will facilitate the clinical translation of gene therapies aimed at the central nervous system.