Science (New York, N.Y.) · 2024
Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Neumann Edwin N, Bertozzi Tessa M, Wu Elaine, Serack Fiona, Harvey John W, Brauer Pamela P, Pirtle Catherine P, Coffey Alissa, Howard Michael, Kamath Nikita, Lenz Kenney, Guzman Kenia, Raymond Michael H, Khalil Ahmad S, Deverman Benjamin E, Minikel Eric Vallabh, Vallabh Sonia M, Weissman Jonathan S
Аннотация
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.