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However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient\u00a0delivery of editors in vivo is needed. To this end, here we targeted\n                    <jats:italic>Pcsk9<\/jats:italic>\n                    , a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse\n                    <jats:italic>Pcsk9<\/jats:italic>\n                    . A single administration of lipid nanoparticles loaded with the editors\u2019 mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably,\n                    <jats:italic>Pcsk9<\/jats:italic>\n                    silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further\u00a0reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07087-8","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T11:02:28Z","timestamp":1709118148000},"page":"416-423","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":195,"title":["Durable and efficient gene silencing in vivo by hit-and-run epigenome editing"],"prefix":"10.1038","volume":"627","author":[{"given":"Martino Alfredo","family":"Cappelluti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Mollica Poeta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0512-1376","authenticated-orcid":false,"given":"Sara","family":"Valsoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3839-3383","authenticated-orcid":false,"given":"Piergiuseppe","family":"Quarato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Merlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Merelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8262-042X","authenticated-orcid":false,"given":"Angelo","family":"Lombardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"7087_CR1","doi-asserted-by":"publisher","first-page":"12453","DOI":"10.1093\/nar\/gkaa1000","volume":"48","author":"A Sgro","year":"2020","unstructured":"Sgro, A. & Blancafort, P. 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