Engineered AAV13 variants with enhanced transduction and confined spread.

IF 4 1区 生物学 Q1 ZOOLOGY
Neng-Song Luo, Yu-Xiang Cai, Zeng-Peng Han, Xiao-Kai Sui, Wen-Jia Yuan, Zi-Lian Zhang, Hao-Dong Guo, Jie Wang, Kun-Zhang Lin, Fu-Qiang Xu
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Abstract

Precise targeting of specific regions within the central nervous system (CNS) is crucial for both scientific research and gene therapy in the context of brain diseases. Adeno-associated virus 13 (AAV13) is known for its restricted diffusion range within the CNS, making it an ideal choice for precise labeling and administration within small brain regions. However, AAV13 mediates relatively low expression of target genes. Here, we introduced specifically engineered modifications to the AAV13 capsid protein to enhance its transduction efficiency. We first constructed AAV13-YF by mutating tyrosine to phenylalanine on the surface of the AAV13 capsid. We then inserted the 7m8 peptide, known to enhance cell transduction, into positions 587/588 and 585/586 of the AAV13 capsid, resulting in two distinct variants named AAV13-587-7m8 and AAV13-585-7m8, respectively. We found that AAV13-YF exhibited superior in vitro infectivity in HEK293T cells compared to AAV13, while AAV13-587-7m8 and AAV13-585-7m8 showed enhanced CNS infection capabilities in C57BL/6 mice, with AAV13-587-7m8 infection retaining a limited spread range. These modified AAV13 variants hold promising potential for applications in gene therapy and neuroscience research.

工程化 AAV13 变体,可增强转导和限制传播。
精确靶向中枢神经系统(CNS)内的特定区域对于脑部疾病的科学研究和基因治疗都至关重要。众所周知,腺相关病毒 13(AAV13)在中枢神经系统内的扩散范围有限,因此是在小脑区进行精确标记和给药的理想选择。然而,AAV13介导的靶基因表达量相对较低。在此,我们对 AAV13 的囊膜蛋白进行了特异性修饰,以提高其转导效率。首先,我们将 AAV13 荚膜表面的酪氨酸突变为苯丙氨酸,从而构建了 AAV13-YF。然后,我们将已知能增强细胞转导的 7m8 肽插入 AAV13 荚膜的 587/588 和 585/586 位,得到了两个不同的变体,分别命名为 AAV13-587-7m8 和 AAV13-585-7m8。我们发现,与 AAV13 相比,AAV13-YF 在 HEK293T 细胞中表现出更高的体外感染性,而 AAV13-587-7m8 和 AAV13-585-7m8 在 C57BL/6 小鼠中表现出更强的中枢神经系统感染能力,AAV13-587-7m8 感染保留了有限的传播范围。这些改良的 AAV13 变体在基因治疗和神经科学研究中具有广阔的应用前景。
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来源期刊
Zoological Research
Zoological Research Medicine-General Medicine
CiteScore
7.60
自引率
10.20%
发文量
1937
审稿时长
8 weeks
期刊介绍: Established in 1980, Zoological Research (ZR) is a bimonthly publication produced by Kunming Institute of Zoology, the Chinese Academy of Sciences, and the China Zoological Society. It publishes peer-reviewed original research article/review/report/note/letter to the editor/editorial in English on Primates and Animal Models, Conservation and Utilization of Animal Resources, and Animal Diversity and Evolution.
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