{"doi":"10.1126/science.ado7082","title":"Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor","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.","journal":"Science","year":2024,"id":416706,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":106,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":463351,"name":"Tessa M. Bertozzi","orcid":"0000-0003-2900-6740","position":1,"is_corresponding":false},{"id":1201953,"name":"Elaine Wu","orcid":null,"position":2,"is_corresponding":false},{"id":1201272,"name":"Fiona E. Serack","orcid":"0000-0001-7377-219X","position":3,"is_corresponding":false},{"id":452831,"name":"John W. Harvey","orcid":"0000-0002-6125-0041","position":4,"is_corresponding":false},{"id":985946,"name":"Pamela P. Brauer","orcid":null,"position":5,"is_corresponding":false},{"id":1201273,"name":"Catherine P. Pirtle","orcid":"0009-0008-4531-5328","position":6,"is_corresponding":false},{"id":1201954,"name":"Alissa A Coffey","orcid":null,"position":7,"is_corresponding":false},{"id":1201955,"name":"Michael W. Howard","orcid":null,"position":8,"is_corresponding":false},{"id":1201956,"name":"Nikita Kamath","orcid":null,"position":9,"is_corresponding":false},{"id":1201957,"name":"Kenney Lenz","orcid":null,"position":10,"is_corresponding":false},{"id":1201958,"name":"Kenia Guzman","orcid":null,"position":11,"is_corresponding":false},{"id":410992,"name":"Michael H. Raymond","orcid":"0000-0003-0754-9517","position":12,"is_corresponding":false},{"id":301193,"name":"Ahmad S. Khalil","orcid":"0000-0002-8214-0546","position":13,"is_corresponding":false},{"id":245910,"name":"Benjamin E. Deverman","orcid":"0000-0002-6223-9303","position":14,"is_corresponding":false},{"id":996,"name":"Eric Vallabh Minikel","orcid":"0000-0003-2206-1608","position":15,"is_corresponding":false},{"id":260620,"name":"Sonia M. Vallabh","orcid":"0000-0003-3824-2702","position":16,"is_corresponding":false},{"id":17890,"name":"Jonathan S. Weissman","orcid":"0000-0003-2445-670X","position":17,"is_corresponding":false},{"id":628568,"name":"Edwin N. Neumann","orcid":"0000-0003-4341-9816","position":0,"is_corresponding":true}],"reference_count":119,"raw_metadata":null,"created_at":"2026-07-19T01:56:44.873714Z","pmid":"38935715","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}