人细胞表面AAV相互作用体将LRP6鉴定为血脑屏障转运受体，将免疫细胞因子IL3鉴定为AAV9结合剂-动脉网

Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

Nature 等信源发布 2024-09-08 01:19

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AbstractAdeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs.

摘要腺相关病毒（AAV）是基础科学和临床治疗的基础基因传递工具。然而，缺乏机械洞察力，特别是对于定向进化产生的工程载体，可能会阻碍其应用。在这里，我们采用无偏见的人类细胞微阵列平台来确定天然和工程AAV的细胞外和细胞表面相互作用组。

We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration.

我们确定了AAV9衣壳和人白细胞介素3（IL3）之间的自然进化和血清型特异性相互作用，可能在宿主免疫调节中发挥作用，以及实验室进化的低密度脂蛋白受体相关蛋白6（LRP6）相互作用。静脉内给药后，非人类灵长类动物的工程衣壳具有增强的血脑屏障穿越。

The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors’ peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites.

无偏细胞微阵列筛选方法还使我们能够鉴定工程化富含大脑的AAV衣壳的脱靶组织结合相互作用，这可能会告知载体的外周器官趋向性和副作用。我们的衣壳相互作用复合物的低温电子断层扫描和AlphaFold建模揭示了LRP6和IL3结合位点。

These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain..

这些结果使工程化AAV在不同生物体中得到了可靠的应用，并为未来改进的病毒和非病毒载体的靶向工程解锁，以实现向大脑的非侵入性治疗。。

IntroductionAdeno-associated viruses (AAVs) have become the gene delivery vector of choice at the bench and in the clinic1,2. Systemic administration of AAVs, such as AAV93,4,5,6, allows noninvasive gene delivery, particularly in large or distributed biological structures7, but access to the brain from the periphery is restricted by the blood-brain barrier (BBB), a complex biological structure that regulates molecular access to the central nervous system (CNS)8,9,10.

引言腺相关病毒（AAV）已成为实验室和临床上首选的基因传递载体1,2。AAVs的全身给药，如AAV93,4,5,6，允许非侵入性基因传递，特别是在大型或分布式生物结构中7，但从外周进入大脑受到血脑屏障（BBB）的限制，血脑屏障是一种复杂的生物结构，调节分子进入中枢神经系统（CNS）8,9,10。

Systemic administration of AAVs also exposes the vectors to the host immune system11,12 and off-target tissues3,13. The poor efficiency of brain targeting after systemic administration with natural serotypes often necessitates high doses that raise costs and may trigger serious adverse events14,15,16.

AAV的全身给药还将载体暴露于宿主免疫系统11,12和脱靶组织3,13。用天然血清型全身给药后大脑靶向的效率低下通常需要高剂量，这会增加成本，并可能引发严重的不良事件14,15,16。

Thus, improved vectors are needed if AAV gene therapy is to realize its full therapeutic potential.AAV capsid engineering, particularly through directed evolution methods, has demonstrated that markedly improved efficiency in desired cell types and tissues after systemic intravenous delivery is possible17,18,19.

因此，如果AAV基因治疗要实现其全部治疗潜力，则需要改进的载体。AAV衣壳工程，特别是通过定向进化方法，已经证明全身静脉内递送后所需细胞类型和组织的效率显着提高是可能的17,18,19。

In particular, two recently identified engineered capsids, AAV9-X1.120 and AAV.CAP-Mac21, robustly transduce CNS neurons after systemic administration in macaques. As AAV capsids are applied across species, however, the enhanced tropisms of many engineered vectors can vary20,21,22,23. This is concerning for human clinical trials, as a capsid developed in another species that performs poorly when translated to humans may not only fail to provide therapeutic benefit but might preclude future therapies for the patient by inducing neutralizing antibodies11.This translational challenge of AAV engineering through directed evolution also represents an opportunity to better understand fundamental mechanisms of.

特别是，最近发现的两种工程衣壳AAV9-X1.120和AAV。CAP-Mac21在猕猴全身给药后强烈转导中枢神经系统神经元。然而，随着AAV衣壳在物种间的应用，许多工程载体的增强趋向性可以变化20,21,22,23。这与人类临床试验有关，因为在另一个物种中开发的衣壳在转化为人类时表现不佳，不仅可能无法提供治疗益处，而且可能通过诱导中和抗体来排除患者未来的治疗11。AAV工程的这种转化挑战通过定向进化也代表了更好地理解其基本机制的机会。

Lrp6 conditional knockout tissue preparation and imagingMice were anesthetized with Euthasol (pentobarbital sodium and phenytoin sodium solution, Virbac AH) and transcardially perfused with approximately 50 mL of 0.1 M PBS, pH 7.4 followed by an equal volume of 4% paraformaldehyde (PFA) in 0.1 M PBS.

Lrp6条件性敲除组织制备和成像用Euthasol（戊巴比妥钠和苯妥英钠溶液，Virbac AH）麻醉小鼠，并用约50ml的0.1M PBS（pH 7.4）经心脏灌注，然后用等体积的4%多聚甲醛（PFA）在0.1M PBS中灌注。

Collected organs were post-fixed in 4% PFA overnight at 4 °C, washed, and stored in 0.1 M PBS with 0.05% sodium azide at 4 °C. A Leica VT1200 vibratome was used to prepare 100 μm brain sections that were imaged on a Zeiss LSM 880 confocal microscope using a Plan-Apochromat 10 × 0.45 M27 (working distance, 2.0 mm) objective.

将收集的器官在4%PFA中于4℃后固定过夜，洗涤，并在4℃下储存在含有0.05%叠氮化钠的0.1M PBS中。使用Leica VT1200振动刀制备100μm脑切片，使用Plan-Apochromat 10×0.45 M27（工作距离，2.0 mm）物镜在Zeiss LSM 880共聚焦显微镜上成像。

Images were analyzed in Zen Black 2.3 SP1 (Zeiss) and ImageJ.AlphaFold structure modelingThe complex structures of the LRP6 extracellular domain and AAV-X1 or AAV.CAP-Mac VR-VIII peptide were modeled using a cloud-based implementation of AlphaFold-Multimer-v352 provided in ColabFold v2.3.596. The input comprised two sequences: surface-exposed residues in VR-VIII of AAV-X1 (587-AQGNNTRSVAQAQTG-594) or AAV-CAP-Mac (587-AQLNTTKPIAQAQTG-594) and the extracellular domain of human LRP6 (UniProt entry O75581, residues 20-1370).

在Zen Black 2.3 SP1（Zeiss）和ImageJ中分析了图像。AlphaFold结构模拟LRP6细胞外结构域和AAV-X1或AAV的复杂结构。使用ColabFold v2.3.596中提供的基于云的AlphaFold-Multimer-v352实现对CAP-Mac VR-VIII肽进行建模。输入包括两个序列：AAV-X1（587-AQGNNTRSVAQTG-594）或AAV-CAP-Mac（587-AQLNTTKPIAQAQTG-594）的VR-VIII中的表面暴露残基和人LRP6的细胞外结构域（UniProt条目O75581，残基20-1370）。

We ran the Google Colaboratory notebook using an A100 SXM4 40GB GPU. Five structure models were produced using a protocol with up to 20 recycles, and MSA generated with MMseqs2 (UniRef+Environmental)97 and templates from PDB70. The structure models were ranked using a weighted combination of pTM and iPTM scores as described in52.

我们使用A100 SXM4 40GB GPU运行了谷歌协作笔记本。使用具有多达20个再循环的协议产生了五个结构模型，并使用MMseqs2（UniRef+Environmental）97和PDB70的模板生成了MSA。如52所述，使用pTM和iPTM分数的加权组合对结构模型进行排名。

All structure visualizations in figures were prepared using PyMOL (www.pymol.org).Statistics & reproducibilityNo statistical methods were performed, including to predetermine sample size, and no data were excluded. Experiments were not randomized and the investigators were not blinded to allocation during experi.

图中的所有结构可视化均使用PyMOL（www.PyMOL.org）制备。统计和可重复性没有进行统计方法，包括预先确定样本量，也没有排除数据。实验不是随机的，研究人员在实验期间也不盲目分配。

Data availability

数据可用性

Cryo-ET data has been deposited to the EMDB with accession codes EMD-42063 (I1 map) [https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-42063] and EMD-41918 (trimer face) [https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-41918]. Cross-linking mass spectrometry data has been deposited to the ProteomeXchange Consortium via the PRIDE84 partner repository with the dataset identifier PXD045380.

Cryo ET数据已保存到EMDB，登录号为EMD-42063（I1 map）[https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-42063]和EMD-41918（三聚体表面）[https://www.ebi.ac.uk/pdbe/entry/emdb/EMD-41918]。交联质谱数据已通过PRIDE84合作伙伴存储库保存到ProteomeXchange Consortium，数据集标识符为PXD045380。

All other data supporting the findings of this study are provided as source data files. Previously published data used in the present study include: IL3 structure, PDB ID: 5UV8; AAV9 structure, PDB ID: 3UX1. Source data are provided with this paper..

支持本研究结果的所有其他数据均作为源数据文件提供。本研究中使用的先前公布的数据包括：IL3结构，PDB ID:5UV8；AAV9结构，PDB ID:3UX1。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank Catherine Oikonomou for help with manuscript editing. We thank Helen McBride for assistance in establishing collaborations with Charles River Laboratories, Brad Gartland and Lynsey Chatham of Charles River Laboratories for technical assistance, and Máté Borsos for assistance breeding Lrp6 conditional KO mice and providing AAV8 and AAVrh10.

下载参考文献致谢我们感谢Catherine Oikonomou在稿件编辑方面的帮助。我们感谢海伦·麦克布莱德（HelenMcBride）协助与查尔斯河实验室（CharlesRiver Laboratories）建立合作关系，感谢查尔斯河实验室（CharlesRiver Laboratories）的布拉德·加特兰（BradGartland）和林西·查塔姆（LynseyChatham）提供技术援助，感谢MátéBorsos协助培育Lrp6条件性KO小鼠并提供AAV8和AAVrh10。

We thank Nathan Appling for helpful discussion. Cryo-electron microscopy was performed in the Beckman Institute Resource Center for Transmission Electron Microscopy at Caltech. Cross-linking mass spectrometry was performed in the Beckman Institute Proteome Exploration Laboratory. Surface plasmon resonance was performed in the Beckman Institute Protein Expression Center.

我们感谢Nathan Appling的有益讨论。低温电子显微镜是在加州理工学院贝克曼研究所透射电子显微镜资源中心进行的。交联质谱法在贝克曼研究所蛋白质组探索实验室进行。。

Figures were created using imagery from BioRender. This project was supported by the Center for Molecular and Cellular Neuroscience in the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech (to V.G.), the Beckman Institute CLOVER Center (to T.F.S. and V.G.), NIH PIONEER DP1NS111369 (to V.G.), and NIH BRAIN Initiative Armamentarium UF1MH128336 (to V.G.

数字是使用BioRender的图像创建的。该项目得到了天桥分子与细胞神经科学中心和加州理工学院Chrissy Chen神经科学研究所（致V.G.），贝克曼研究所三叶草中心（致T.F.S.和V.G.），NIH先驱DP1NS111369（致V.G.）和NIH脑倡议武器库UF1MH128336（致V.G.）的支持。

and T.F.S.).Author informationAuthor notesThese authors contributed equally: Timothy F. Shay, Seongmin Jang, Tyler J. Brittain, Xinhong Chen.Authors and AffiliationsDivision of Biology & Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USATimothy F. Shay, Seongmin Jang, Tyler J.

和T.F.S.）。作者信息作者注意到这些作者做出了同样的贡献：Timothy F.Shay，Seongmin Jang，Tyler J.Brittain，Xinhong Chen。作者和附属机构加利福尼亚理工学院生物与生物工程系，加利福尼亚州帕萨迪纳，91125，USATimothy F.Shay，Seongmin Jang，Tyler J。

Brittain, Xinhong Chen, Yujie Fan, Damien A. Wolfe, Cynthia M. Arokiaraj, Erin E. Sullivan, Xiaozhe Ding, Ting-Yu Wang, Yaping Lei, Miguel R. Chuapoco, Tsui-Fen Chou & Viviana GradinaruCharles River Laboratories, High Peak Business Park, Buxton Road, Chinley, SK23 6FJ, UKBeth Walker & Claire TebbuttAuthorsTimothy F.

Brittain，Xinhong Chen，Yujie Fan，Damien A.Wolfe，Cynthia M.Arokiaraj，Erin E.Sullivan，Xiaozhe Ding，Ting Yu Wang，Yaping Lei，Miguel R.Chuapoco，Tsui Fen Chou&Viviana GradinaruCharles River Laboratories，High Peak Business Park，Buxton Road，Chinley，SK23 6FJ，UKBeth Walker&Claire TebbuthorsTimothy F。

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PubMed Google ScholarContributionsT.F.S., S.J., and V.G. conceived the project. T.F.S., S.J., and V.G. wrote the manuscript and prepared figures with input from all authors. T.F.S., X.C., E.E.S., Y.L., S.J., and M.R.C. produced AAVs. B.W. and C.T. performed cell microarray screening.

PubMed谷歌学术贡献者。F、。T、 F.S.，S.J。和V.G.撰写了手稿，并根据所有作者的意见准备了数字。T、 F.S.，X.C.，E.E.S.，Y.L.，S.J。和M.R.C.生产了AAV。B、 W.和C.T.进行了细胞微阵列筛选。

S.J. produced recombinant receptor protein and performed pull-down assays, T.J.B., T.Y.W., and T.F.C. performed cross-linking mass spectrometry experiments. C.M.A. and E.E.S performed cell culture potency assays. T.F.S. and S.J. performed SPR experiments. X.D. performed AlphaFold modeling. X.C. and D.A.W.

S、 J.产生重组受体蛋白并进行下拉测定，T.J.B.，T.Y.W。和T.F.C.进行交联质谱实验。C、 M.A.和E.E.S进行了细胞培养效力测定。T、。十、 D.进行AlphaFold建模。十、 C.和D.A.W。

performed mouse experiments. X.C. performed primary cell culture experiments. T.J.B. collected and T.J.B. and S.J. analyzed cryo-electron tomography data. Y.F. performed hPSC cell culture experiments. T.F.S and V.G. supervised and funded the project.Corresponding authorsCorrespondence to.

进行了小鼠实验。十、 C.进行原代细胞培养实验。T、 J.B.收集并分析了低温电子断层扫描数据。Y、 F.进行hPSC细胞培养实验。T、 F.S和V.G.监督并资助了该项目。通讯作者通讯。

Timothy F. Shay or Viviana Gradinaru.Ethics declarations

蒂莫西·谢伊（TimothyF.Shay）或维维亚娜·格拉迪纳鲁（VivianaGradinaru）。道德宣言

Competing interests

相互竞争的利益

The California Institute of Technology has a patent pending for the delivery methods identified in this manuscript, with T.F.S, X.C., S.J., and V.G. listed as inventors (PCT Patent Application No: PCT/US2024/0139329) and a provisional patent for the sequences described in this manuscript, with S.J., T.J.B., T.F.S., and V.G listed as inventors.

。

V.G. is a co-founder and board of directors member of Capsida Therapeutics, a fully integrated AAV engineering and gene therapy company. T.F.S and V.G. are co-founders and X.C. and X.D. are co-founders and employees of Receptive Biotherapeutics. B.W. and C.T. are employees of Charles River Laboratories.

五、 G.是Capsida Therapeutics的联合创始人和董事会成员，Capsida Therapeutics是一家全面整合的AAV工程和基因治疗公司。T、 F.S和V.G.是联合创始人，X.C.和X.D.是接受性生物治疗学的联合创始人和员工。B、 W.和C.T.是查尔斯河实验室的员工。

The remaining authors declare no competing interests..

其余作者声明没有利益冲突。。

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Reprints and permissionsAbout this articleCite this articleShay, T.F., Jang, S., Brittain, T.J. et al. Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder.

转载和许可本文引用本文Shay，T.F.，Jang，S.，Brittain，T.J。等人。人类细胞表面AAV相互作用组将LRP6鉴定为血脑屏障转胞吞作用受体，将免疫细胞因子IL3鉴定为AAV9粘合剂。

Nat Commun 15, 7853 (2024). https://doi.org/10.1038/s41467-024-52149-0Download citationReceived: 06 June 2024Accepted: 27 August 2024Published: 08 September 2024DOI: https://doi.org/10.1038/s41467-024-52149-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》157853（2024）。https://doi.org/10.1038/s41467-024-52149-0Download引文接收日期：2024年6月6日接受日期：2024年8月27日发布日期：2024年9月8日OI：https://doi.org/10.1038/s41467-024-52149-0Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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