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Display of Self-Peptide on Adeno-Associated Virus Capsid Decreases Phagocytic Uptake in Vitro.
ACS Synthetic Biology ( IF 3.7 ) Pub Date : 2020-08-31 , DOI: 10.1021/acssynbio.0c00203
Tawana M Robinson 1 , Maria Y Chen 2 , Michael T Lam 2 , Matthew R Ykema 2 , Junghae Suh 2, 3, 4, 5
Affiliation  

Adeno-associated virus (AAV) vectors are currently investigated as gene transfer agents for the treatment of a variety of diseases. However, activation of the host immune response upon vector administration limits the use of AAV in the clinical setting. To decrease host detection of AAVs, we tested the CD47-based “don’t-eat-me” signal in the context of the AAV capsid. We genetically incorporated the bioactive region of CD47, named “self-peptide” (SP), onto the surface of the AAV2 capsid. AAV mutants were structurally and functionally characterized for vector production, SP and linker incorporation into the capsid, transduction efficiency, and phagocytic susceptibility. We demonstrate that utilizing linkers improves the AAV2 capsid’s tolerance to SP insertion. Notably, the SP significantly decreases the phagocytic susceptibility of AAV2 in vitro. Collectively, these results suggest that display of the SP motif on the AAV capsid surface can inhibit phagocytosis of the vector in vitrovia the “don’t-eat-me” signaling.

中文翻译:

在腺相关病毒衣壳上展示自身肽会降低体外吞噬细胞的摄取。

目前正在研究腺相关病毒 (AAV) 载体作为用于治疗多种疾病的基因转移剂。然而,载体给药后宿主免疫反应的激活限制了 AAV 在临床环境中的使用。为了减少 AAV 的宿主检测,我们在 AAV 衣壳的背景下测试了基于 CD47 的“不要吃我”信号。我们通过基因将 CD47 的生物活性区域(称为“自肽”(SP))整合到 AAV2 衣壳的表面。AAV 突变体在结构和功能上的特征在于载体生产、SP 和接头掺入衣壳、转导效率和吞噬敏感性。我们证明利用接头可以提高 AAV2 衣壳对 SP 插入的耐受性。值得注意的是,SP 显着降低了 AAV2 的吞噬敏感性体外。总的来说,这些结果表明,在 AAV 衣壳表面展示 SP 基序可以通过“不要吃我”信号抑制体外载体的吞噬作用。
更新日期:2020-09-20
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