Durable and efficient gene silencing in vivo by hit-and-run epigenome editing

Martino Alfredo Cappelluti, Valeria Mollica Poeta, Sara Valsoni, Piergiuseppe Quarato, Simone Merlin, Ivan Merelli and Angelo Lombardo ()
Additional contact information
Martino Alfredo Cappelluti: IRCCS San Raffaele Scientific Institute
Valeria Mollica Poeta: IRCCS San Raffaele Scientific Institute
Sara Valsoni: IRCCS San Raffaele Scientific Institute
Piergiuseppe Quarato: IRCCS San Raffaele Scientific Institute
Simone Merlin: Università del Piemonte Orientale
Ivan Merelli: IRCCS San Raffaele Scientific Institute
Angelo Lombardo: IRCCS San Raffaele Scientific Institute

Nature, 2024, vol. 627, issue 8003, 416-423

Abstract: Abstract Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases1–3. However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9, 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 Pcsk9. A single administration of lipid nanoparticles loaded with the editors’ mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 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 reduced 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07087-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:627:y:2024:i:8003:d:10.1038_s41586-024-07087-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07087-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().