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.

中文翻译：

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通过 AAV 介导的工程紧凑表观遗传编辑器的传递实现全脑沉默朊病毒蛋白


朊病毒病是由朊病毒蛋白（PrP）错误折叠成致病性自我繁殖构象引起的，导致快速发作的痴呆和死亡。然而，消除内源性 PrP 可以阻止朊病毒疾病的进展。在这项研究中，我们描述了用于甲基转移酶自动抑制释放的耦合组蛋白尾 (CHARM)，这是一种紧凑的、无酶的表观遗传编辑器，能够通过可编程 DNA 甲基化来沉默转录。利用组蛋白 H3 尾部-Dnmt3l 融合，CHARM 招募并激活内源 DNA 甲基转移酶，从而减少转基因大小和细胞毒性。当通过全身注射腺相关病毒 (AAV) 递送至小鼠大脑时，Prnp 靶向 CHARM 会消除整个大脑中的 PrP 表达。此外，我们通过实施动力学调整的自沉默方法来暂时限制编辑器的表达。 CHARM 可能代表了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蛋白。