Durable and efficient gene silencing in vivo by hit-and-run epigenome editing DOI Creative Commons
Martino Alfredo Cappelluti, Valeria Mollica Poeta, Sara Valsoni

et al.

Nature, Journal Year: 2024, Volume and Issue: 627(8003), P. 416 - 423

Published: Feb. 28, 2024

Abstract Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases 1–3 . However, to unlock its full therapeutic potential, an experimental confirmation durable after delivery transient in vivo is needed. To this end, here we targeted Pcsk9 , a gene expressed hepatocytes that involved cholesterol homeostasis. In vitro screening different editor designs indicated zinc-finger proteins were best-performing DNA-binding platform efficient mouse A single administration lipid nanoparticles loaded editors’ mRNAs almost halved circulating levels PCSK9 nearly one year mice. Notably, and accompanying repressive marks also persisted forced liver regeneration, further corroborating heritability newly installed state. Improvements construct design resulted development all-in-one configuration term evolved engineered repressor (EvoETR). This design, which characterized by high specificity profile, reduced mice efficiency comparable obtained through conventional editing, but without causing DNA breaks. Our study lays foundation therapeutics are based on silencing.

Language: Английский

Nano drug delivery systems for antisense oligonucleotides (ASO) therapeutics DOI

Thiruganesh Ramasamy,

Hima Bindu Ruttala, Shankar Munusamy

et al.

Journal of Controlled Release, Journal Year: 2022, Volume and Issue: 352, P. 861 - 878

Published: Nov. 14, 2022

Language: Английский

Citations

71
Clinical delivery of circular RNA: Lessons learned from RNA drug development DOI
Tiana L. Young, Kevin Chang Wang, Andrew Varley

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 197, P. 114826 - 114826

Published: April 23, 2023

Language: Английский

Citations

69
Genetics of human brain development DOI
Yi Zhou, Hongjun Song, Guo‐li Ming

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 26 - 45

Published: July 28, 2023

Language: Английский

Citations

69
Ultrasound technology and biomaterials for precise drug therapy DOI
Zhenyu Zhao, Qimanguli Saiding, Zhengwei Cai

et al.

Materials Today, Journal Year: 2023, Volume and Issue: 63, P. 210 - 238

Published: Jan. 9, 2023

Language: Английский

Citations

68
Durable and efficient gene silencing in vivo by hit-and-run epigenome editing DOI Creative Commons
Martino Alfredo Cappelluti, Valeria Mollica Poeta, Sara Valsoni

et al.

Nature, Journal Year: 2024, Volume and Issue: 627(8003), P. 416 - 423

Published: Feb. 28, 2024

Abstract Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases 1–3 . However, to unlock its full therapeutic potential, an experimental confirmation durable after delivery transient in vivo is needed. To this end, here we targeted Pcsk9 , a gene expressed hepatocytes that involved cholesterol homeostasis. In vitro screening different editor designs indicated zinc-finger proteins were best-performing DNA-binding platform efficient mouse A single administration lipid nanoparticles loaded editors’ mRNAs almost halved circulating levels PCSK9 nearly one year mice. Notably, and accompanying repressive marks also persisted forced liver regeneration, further corroborating heritability newly installed state. Improvements construct design resulted development all-in-one configuration term evolved engineered repressor (EvoETR). This design, which characterized by high specificity profile, reduced mice efficiency comparable obtained through conventional editing, but without causing DNA breaks. Our study lays foundation therapeutics are based on silencing.

Language: Английский

Citations

68