Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors.
Primate-conserved carbonic anhydrase IV and murine-restricted LY6C1 enable blood-brain barrier crossing by engineered viral vectors.
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DOI：
10.1126/sciadv.adg6618
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发表时间：
2023-04-21
期刊：
影响因子：
13.6
通讯作者：
Gradinaru, Viviana
中科院分区：
文献类型：
--
作者：
Shay, Timothy F.;Sullivan, Erin E.;Ding, Xiaozhe;Chen, Xinhong;Kumar, Sripriya Ravindra;Goertsen, David;Brown, David;Crosby, Anaya;Vielmetter, Jost;Wolfe, Damien A.;Lam, Annie W.;Gradinaru, Viviana
血脑屏障（BBB）对输送大分子以研究和治疗中枢神经系统提出了重大挑战。这部分是由于已知介导 BBB 穿越的靶标稀缺。为了确定新的靶标，我们利用了一组先前通过与机制无关的定向进化来识别的腺相关病毒 (AAV)，以改善 BBB 转胞吞作用。通过筛选增强 BBB 交叉的潜在同源受体，我们确定了两个靶标：小鼠限制性 LY6C1 和广泛保守的碳酸酐酶 IV (CA-IV)。我们应用基于 AlphaFold 的计算机方法来生成衣壳-受体结合模型，以预测 AAV 对这些已识别受体的亲和力。为了演示这些工具如何解锁以目标为中心的工程策略，我们创建了一个增强的 LY6C1 结合载体 AAV-PHP.eC，与我们之前的 PHP.eB 不同，它也适用于 Ly6a 缺陷的小鼠品系，例如 BALB/cJ。结合计算模型的结构见解，对灵长类保守 CA-IV 的识别能够设计出更特异、更有效的人脑渗透化学物质和生物制品，包括基因传递载体。保守的受体被确定为工程载体的靶标，以将治疗药物从血流输送到大脑。
The blood-brain barrier (BBB) presents a major challenge for delivering large molecules to study and treat the central nervous system. This is due in part to the scarcity of targets known to mediate BBB crossing. To identify novel targets, we leverage a panel of adeno-associated viruses (AAVs) previously identified through mechanism-agnostic directed evolution for improved BBB transcytosis. Screening potential cognate receptors for enhanced BBB crossing, we identify two targets: murine-restricted LY6C1 and widely conserved carbonic anhydrase IV (CA-IV). We apply AlphaFold-based in silico methods to generate capsid-receptor binding models to predict the affinity of AAVs for these identified receptors. Demonstrating how these tools can unlock target-focused engineering strategies, we create an enhanced LY6C1-binding vector, AAV-PHP.eC, that, unlike our prior PHP.eB, also works in Ly6a-deficient mouse strains such as BALB/cJ. Combined with structural insights from computational modeling, the identification of primate-conserved CA-IV enables the design of more specific and potent human brain–penetrant chemicals and biologicals, including gene delivery vectors. A conserved receptor is identified as a target for engineered vectors to deliver therapeutics to the brain from the bloodstream.
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影响因子：
16.2
作者：
Chen, Xinhong;Kumar, Sripriya Ravindra;Adams, Cameron D.;Yang, Daping;Wang, Tongtong;Wolfe, Damien A.;Arokiaraj, Cynthia M.;Ngo, Victoria;Campos, Lillian J.;Griffiths, Jessica A.;Ichiki, Takako;Mazmanian, Sarkis K.;Osborne, Peregrine B.;Keast, Janet R.;Miller, Cory T.;Fox, Andrew S.;Chiu, Isaac M.;Gradinaru, Viviana
通讯作者：
Gradinaru, Viviana
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V
影响因子：
15.9
作者：
Fleming, RE;Parkkila, S;Sly, WS
通讯作者：
Sly, WS
DOI：
10.1073/pnas.88.11.4771
发表时间：
1991-06-01
影响因子：
11.1
作者：
FRIDEN, PM;WALUS, LR;STARZYK, RM
通讯作者：
STARZYK, RM
DOI：
10.1073/pnas.1910061116
发表时间：
2019-12-26
影响因子：
11.1
作者：
Davidsson, Marcus;Wang, Gang;Bjorklund, Tomas
通讯作者：
Bjorklund, Tomas