Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor-Reference-Cited by-同舟云学术

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

Published:2024-06-28 Issue:6703 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Neumann Edwin N.¹²^ORCID,Bertozzi Tessa M.¹³^ORCID,Wu Elaine¹^ORCID,Serack Fiona⁴^ORCID,Harvey John W.⁴,Brauer Pamela P.⁴,Pirtle Catherine P.⁴^ORCID,Coffey Alissa⁴,Howard Michael⁵,Kamath Nikita⁴,Lenz Kenney⁵,Guzman Kenia⁵^ORCID,Raymond Michael H.⁶⁷^ORCID,Khalil Ahmad S.⁶⁷⁸^ORCID,Deverman Benjamin E.⁴^ORCID,Minikel Eric Vallabh⁴⁹^ORCID,Vallabh Sonia M.⁴⁹^ORCID,Weissman Jonathan S.¹³¹⁰¹¹^ORCID

Affiliation:

1. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

3. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

4. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

5. Comparative Medicine, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

6. Biological Design Center, Boston University, Boston, MA 02215, USA.

7. Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.

8. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

9. McCance Center for Brain Health and Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

10. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

11. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.ado7082

Reference119 articles.

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4. Mice devoid of PrP are resistant to scrapie

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