Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno-Associated Viral Vector rAAV9P1.
Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno-Associated Viral Vector rAAV9P1.
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DOI：
10.1002/advs.202104979
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
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星形胶质细胞在中枢神经系统（CNS）中具有重要的功能，是许多中枢神经系统疾病的主要参与者。星形胶质细胞为中心的疾病的研究需要有效的和充分表征的基因转移载体。来源于腺相关病毒血清型9 （AAV9）的载体靶向啮齿动物和非人灵长类动物大脑中的星形胶质细胞。重组(r)合成肽显示AAV9变体，rAAV9P1，有效和选择性地传导培养的人类星形胶质细胞，之前已经描述过。本研究表明，经小鼠静脉注射后，rAAV9P1保留了星形胶质细胞靶向特性。对人星形胶质细胞上可能受体的详细分析表明，rAAV9P1利用整合素亚基αv、β8、β3或β5以及AAV受体AAVR。这种受体模式不同于野生型AAV2或AAV9衍生的载体。此外，CRISPR/Cas9全基因组敲除筛选揭示了rAAV9P1参与人类星形胶质细胞转导的几个星形胶质细胞相关的细胞内信号通路。本研究描述了rAAV9P1靶向人类星形胶质细胞的独特受体和细胞内通路特征。这些结果增强了对合成rAAV载体在星形胶质细胞转导生物学的认识，并可促进先进的星形胶质细胞选择性基因传递载体的开发，用于研究和临床应用。重组腺相关病毒载体9P1 （rAAV9P1）是AAV9的一种多肽显示变体，可高效靶向人（体外）和小鼠（体内）星形胶质细胞。rAAV9P1利用整合素αvβ8和αvβ3或αvβ5、聚糖残基和AAV受体（AAVR）转导星形胶质细胞。各种星形胶质细胞相关的细胞内通路也有助于rAAV9P1有效地转导星形胶质细胞。
Astrocytes have crucial functions in the central nervous system (CNS) and are major players in many CNS diseases. Research on astrocyte‐centered diseases requires efficient and well‐characterized gene transfer vectors. Vectors derived from the Adeno‐associated virus serotype 9 (AAV9) target astrocytes in the brains of rodents and nonhuman primates. A recombinant (r) synthetic peptide‐displaying AAV9 variant, rAAV9P1, that efficiently and selectively transduces cultured human astrocytes, has been described previously. Here, it is shown that rAAV9P1 retains astrocyte‐targeting properties upon intravenous injection in mice. Detailed analysis of putative receptors on human astrocytes shows that rAAV9P1 utilizes integrin subunits αv, β8, and either β3 or β5 as well as the AAV receptor AAVR. This receptor pattern is distinct from that of vectors derived from wildtype AAV2 or AAV9. Furthermore, a CRISPR/Cas9 genome‐wide knockout screening revealed the involvement of several astrocyte‐associated intracellular signaling pathways in the transduction of human astrocytes by rAAV9P1. This study delineates the unique receptor and intracellular pathway signatures utilized by rAAV9P1 for targeting human astrocytes. These results enhance the understanding of the transduction biology of synthetic rAAV vectors for astrocytes and can promote the development of advanced astrocyte‐selective gene delivery vehicles for research and clinical applications. Recombinant Adeno‐associated virus vector 9P1 (rAAV9P1) is a peptide‐displaying variant of AAV9 that targets human (in vitro) and murine (in vivo) astrocytes with high efficiency. rAAV9P1 utilizes the integrins αvβ8 and αvβ3 or αvβ5, glycan residues and the AAV receptor (AAVR) to transduce astrocytes. Various astrocyte‐relevant intracellular pathways also contribute to efficient transduction of astroyctes by rAAV9P1.
影响因子：
4.4
作者：
Trümbach D;Pfeiffer S;Poppe M;Scherb H;Doll S;Wurst W;Schick JA
通讯作者：
Schick JA
影响因子：
14.9
作者：
Schmid-Burgk JL;Xie Z;Frank S;Virreira Winter S;Mitschka S;Kolanus W;Murray A;Benenson Y
通讯作者：
Benenson Y