核酸修饰可以通过阻断RNase裂变来合理设计TLR7选择性配体
Ann-Jay Tong1, Rebecca Leylek1, Anna-Maria Herzner1
1Genentech, Inc. , South San Francisco, CA, USA.
The Journal of experimental medicine
|December 14, 2023
概括
科学家们开发了修改后的RNA分子,可以选择性地激活关键免疫传感器的Toll-like受体7 (TLR7). 这一策略克服了针对TLR7的挑战,使得免疫反应能够精确地调节.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 在RNA治疗方面,RNA疗法.
背景情况:
- 收费类受体7 (TLR7) 和8 (TLR8) 识别单链RNA (ssRNA),但具有相似的结构,复杂的选择性激活.
- 对于TLR7和TLR8的配体生成涉及ssRNA的内溶性RNase处理.
研究的目的:
- 开发一种使用修饰RNA分子选择性激活TLR7而不是TLR8的方法.
- 调查RNase处理在TLR7激活中的作用.
主要方法:
- 合成具有已知的TLR7/TLR8结合基因的2′糖改性寡核酸 (ORNs).
- 在初级人体血细胞状树突细胞中进行CRISPR-Cas9基因编辑,以评估TLR7依赖性.
- 用小鼠进行体内研究,以评估经过修改的ORN的免疫激活.
主要成果:
- 2'糖修饰防止了RNase降解为TLR8激活尿素,同时保持TLR7激活.
- 证实TLR7的激活依赖于RNase,其中RNase 6被确定为关键酶.
- 修改后的ORN在小鼠中诱导了显著的先天性免疫激活.
结论:
- 通过使用修改的ORN确定了一种创建可调节的TLR7选择性激动剂的策略.
- 这种方法可以精确控制由TLR7调解的免疫反应.
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