Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.
Science
; 384(6703): ado7082, 2024 Jun 28.
Article
in En
| MEDLINE
| ID: mdl-38935715
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Histones
/
Dependovirus
/
DNA Methylation
/
Gene Silencing
/
Prion Proteins
Limits:
Animals
/
Humans
Language:
En
Journal:
Science
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos