调节 AAV9 的半乳糖结合可产生新的基因治疗载体,并可预测糖酶活性的跨物种差异。

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-09-01 Epub Date: 2024-08-13 DOI:10.1089/hum.2024.050
Jacob A Hoffman, Nathan Denton, Joshua J Sims, Rosemary Meggersee, Zhe Zhang, Kanyin Olagbegi, James M Wilson
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引用次数: 0

摘要

由于腺相关病毒(AAV)容易在肝脏中蓄积并转导肝脏,因此限制了其在临床基因治疗中的有效使用。在肝外组织中实现治疗性转基因表达所需的高剂量下,这种天然的肝脏趋向性与严重的不良反应有关。为了提高 AAV 基因治疗的安全性并降低成本,我们正在进行囊壳工程研究,以改变 AAV 在体内的生物分布,使其从肝脏转向心脏等与疾病相关的外周器官。在先前工作的基础上,我们生成了一系列 AAV 文库,其中包含 AAV9 VP1 蛋白半乳糖结合袋三个残基(Y446、N470 和 W503)的变异。在小鼠体内筛选该文库发现了 XRH 系列变体(Y446X、N470R 和 W503H),其中最强的变体 HRH 与小鼠体内的野生型 AAV9 相比,肝脏 RNA 表达量减少了六倍,心脏 RNA 表达量增加了十倍。在非人灵长类动物(NHP)中对我们的文库进行筛选后发现,与小鼠肝脏相比,AAV9 和两种密切相关的载体在 NHP 肝脏中的表现有所下降。对我们文库的半乳糖结合能力的测定进一步确定了这三种载体是唯一的强半乳糖结合体,这表明小鼠和非人灵长类肝脏中的半乳糖表达发生了改变。这些组织的 N-糖谱分析显示,与小鼠肝脏相比,NHP 肝脏中暴露的半乳糖减少了 9%。在这项工作中,我们发现了一系列新型 AAV 变体,它们具有理想的生物分布特性,可能适合靶向心脏等肝外组织。这些数据还提供了关于物种和组织特异性糖表达差异的重要见解,可能会对 AAV 基因疗法的开发和转化产生影响。
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Modulation of AAV9 Galactose Binding Yields Novel Gene Therapy Vectors and Predicts Cross-Species Differences in Glycan Avidity.

Effective use of adeno-associated viruses (AAVs) for clinical gene therapy is limited by their propensity to accumulate in and transduce the liver. This natural liver tropism is associated with severe adverse events at the high doses that can be necessary for achieving therapeutic transgene expression in extrahepatic tissues. To improve the safety and cost of AAV gene therapy, capsid engineering efforts are underway to redirect in vivo AAV biodistribution away from the liver toward disease-relevant peripheral organs such as the heart. Building on previous work, we generated a series of AAV libraries containing variations at three residues (Y446, N470, and W503) of the galactose-binding pocket of the AAV9 VP1 protein. Screening of this library in mice identified the XRH family of variants (Y446X, N470R, and W503H), the strongest of which, HRH, exhibited a 6-fold reduction in liver RNA expression and a 10-fold increase in cardiac RNA expression compared with wild-type AAV9 in the mouse. Screening of our library in a nonhuman primate (NHP) revealed reduced performance of AAV9 and two closely related vectors in the NHP liver compared with the mouse liver. Measurement of the galactose-binding capacity of our library further identified those same three vectors as the only strong galactose binders, suggesting an altered galactose presentation between the mouse and NHP liver. N-glycan profiling of these tissues revealed a 9% decrease in exposed galactose in the NHP liver compared with the mouse liver. In this work, we identified a novel family of AAV variants with desirable biodistribution properties that may be suitable for targeting extrahepatic tissues such as the heart. These data also provide important insights regarding species- and tissue-specific differences in glycan presentation that may have implications for the development and translation of AAV gene therapies.

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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
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