Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.

Autor: Neumann EN; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Bertozzi TM; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA., Wu E; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA., Serack F; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Harvey JW; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Brauer PP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pirtle CP; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Coffey A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Howard M; Comparative Medicine, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Kamath N; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Lenz K; Comparative Medicine, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Guzman K; Comparative Medicine, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Raymond MH; Biological Design Center, Boston University, Boston, MA 02215, USA.; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA., Khalil AS; Biological Design Center, Boston University, Boston, MA 02215, USA.; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA., Deverman BE; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Minikel EV; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA., Vallabh SM; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA., Weissman JS; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Jun 28; Vol. 384 (6703), pp. ado7082. Date of Electronic Publication: 2024 Jun 28.
DOI: 10.1126/science.ado7082
Abstrakt: 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.
Databáze: MEDLINE
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