小柯机器人

美国麻省理工学院Jonathan S. Weissman等研究人员合作通过AAV介导的工程化紧凑型表观遗传编辑器在全脑范围内沉默朊病毒蛋白。2024年6月28日，国际知名学术期刊《科学》发表了这一成果。

研究人员描述了用于自动抑制释放甲基转移酶的偶联组蛋白尾（CHARM），这是一种结构紧凑、不含酶的表观遗传编辑器，能够通过可编程的DNA甲基化来沉默转录。CHARM利用组蛋白H3尾部-Dnmt3l融合，招募并激活内源性DNA甲基转移酶，从而减少转基因的大小和细胞毒性。当通过全身注射腺相关病毒（AAV）将朊病毒蛋白（PrP）靶向CHARM送入小鼠大脑时，它能消除整个大脑的PrP表达。

此外，研究人员还通过实施一种动态调整的自我沉默方法，在时间上限制了编辑器的表达。CHARM可能是一种广泛适用的抑制致病蛋白的策略，包括那些与其他神经退行性疾病有关的致病蛋白。

据介绍，朊病毒病是由PrP错误地折叠成致病的自传播构象引起的，导致快速发病的痴呆和死亡。然而，消除内源性PrP可以阻止朊病毒病的发展。

附：英文原文

Title: Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor

Author: Edwin N. Neumann, Tessa M. Bertozzi, Elaine Wu, Fiona Serack, John W. Harvey, Pamela P. Brauer, Catherine P. Pirtle, Alissa Coffey, Michael Howard, Nikita Kamath, Kenney Lenz, Kenia Guzman, Michael H. Raymond, Ahmad S. Khalil, Benjamin E. Deverman, Eric Vallabh Minikel, Sonia M. Vallabh, Jonathan S. Weissman

Issue&Volume: 2024-06-28

Abstract: Prion disease is caused by misfolding of the prion protein (PrP) into pathogenic self-propagating conformations, leading to rapid-onset dementia and death. However, elimination of endogenous PrP halts prion disease progression. In this study, we describe Coupled Histone tail for Autoinhibition Release of Methyltransferase (CHARM), a compact, enzyme-free epigenetic editor capable of silencing transcription through programmable DNA methylation. Using a histone H3 tail-Dnmt3l fusion, CHARM recruits and activates endogenous DNA methyltransferases, thereby reducing transgene size and cytotoxicity. When delivered to the mouse brain by systemic injection of adeno-associated virus (AAV), Prnp-targeted CHARM ablates PrP expression across the brain. Furthermore, we have temporally limited editor expression by implementing a kinetically tuned self-silencing approach. CHARM potentially represents a broadly applicable strategy to suppress pathogenic proteins, including those implicated in other neurodegenerative diseases.

DOI: ado7082

Source: https://www.science.org/doi/10.1126/science.ado7082