Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

Markus Grosch, Laura Schraft, Adrian Chan, Leonie Küchenhoff, Kleopatra Rapti, Anne-Maud Ferreira, Julia Kornienko, Shengdi Li, Michael H. Radke, Chiara Krämer, Sandra Clauder-Münster, Emerald Perlas, Johannes Backs, Michael Gotthardt, Christoph Dieterich, Maarten M. G. Hoogenhof, Dirk Grimm and Lars M. Steinmetz ()
Additional contact information
Markus Grosch: Genome Biology Unit
Laura Schraft: Genome Biology Unit
Adrian Chan: University of Heidelberg
Leonie Küchenhoff: Genome Biology Unit
Kleopatra Rapti: University of Heidelberg
Anne-Maud Ferreira: Stanford University School of Medicine
Julia Kornienko: Genome Biology Unit
Shengdi Li: Genome Biology Unit
Michael H. Radke: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Chiara Krämer: University of Heidelberg
Sandra Clauder-Münster: Genome Biology Unit
Emerald Perlas: Epigenetics and Neurobiology Unit, EMBL Rome
Johannes Backs: DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim
Michael Gotthardt: Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Christoph Dieterich: DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim
Maarten M. G. Hoogenhof: DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim
Dirk Grimm: DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim
Lars M. Steinmetz: Genome Biology Unit

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Dilated cardiomyopathy is the second most common cause for heart failure with no cure except a high-risk heart transplantation. Approximately 30% of patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related to delivery of the editing complex and off-target concerns hamper the broad applicability of CRISPR agents in the heart. We employ a combination of the viral vector AAVMYO with superior targeting specificity of heart muscle tissue and CRISPR base editors to repair patient mutations in the cardiac splice factor Rbm20, which cause aggressive dilated cardiomyopathy. Using optimized conditions, we repair >70% of cardiomyocytes in two Rbm20 knock-in mouse models that we have generated to serve as an in vivo platform of our editing strategy. Treatment of juvenile mice restores the localization defect of RBM20 in 75% of cells and splicing of RBM20 targets including TTN. Three months after injection, cardiac dilation and ejection fraction reach wild-type levels. Single-nuclei RNA sequencing uncovers restoration of the transcriptional profile across all major cardiac cell types and whole-genome sequencing reveals no evidence for aberrant off-target editing. Our study highlights the potential of base editors combined with AAVMYO to achieve gene repair for treatment of hereditary cardiac diseases.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-39352-1 Abstract (text/html)

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:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39352-1

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

DOI: 10.1038/s41467-023-39352-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

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