通过撞击和逃跑的表观基因组编辑,在体内持续有效的基因沉默
Martino Alfredo Cappelluti1, Valeria Mollica Poeta1, Sara Valsoni1
1San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Nature
|February 28, 2024
概括
短暂的表观遗传编辑器可以使小鼠的Pcsk9基因在长达一年的时间内保持沉默,为无需DNA断裂的体内治疗提供了一个有希望的新途径.
科学领域:
- 表观遗传学
- 基因调控
- 分子疗法
背景情况:
- 通过转录抑制剂永久性表观遗传沉默显示出对疾病的治疗潜力.
- 在传递过渡编辑器后,对持久沉默的体内确认至关重要.
研究的目的:
- 通过可编程编辑器研究Pcsk9基因的耐久表观遗传沉默.
- 评估暂时输送的表观遗传沉默剂的治疗潜力.
主要方法:
- 指蛋白作为Pcsk9沉默的DNA结合平台的选.
- 在小鼠体内给予携带针对Pcsk9的编辑器mRNA的脂质纳米颗粒.
- 开发和测试一个全合一的进化工程转录抑制器 (EvoETR) 结构.
主要成果:
- 一次通过脂质纳米颗粒的编辑剂在小鼠中将近一年的循环PCSK9水平降低了近50%.
- 经过肝脏再生,表观遗传沉默和抑制痕迹持续存在, 证实了遗传性.
- 在没有诱导DNA断裂的情况下,EvoETR结构实现了高特异性和高效的PCSK9减少.
结论:
- 短暂的表观遗传编辑器可以在体内实现持久的基因沉默.
- 进化的转录抑制剂为表观遗传疗法提供了安全有效的平台.
- 这项研究为开发体内表观遗传沉默疗法奠定了基础.
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