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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Boston University; Boston University; Harvard University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13452
• DOI: 10.1126/science.ado7082
• 发表日期: 2024-06-28
• 关键词: in-vivo delivery; dna methylation; transcription; DESIGN; dnmt3a; lacking; mice; prp; technologies; selection

摘要

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.