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

Autor: Grosch M; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Schraft L; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Chan A; Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany., Küchenhoff L; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Rapti K; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, BioQuant, University of Heidelberg, Heidelberg, Germany., Ferreira AM; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Kornienko J; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany., Li S; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Radke MH; Translational Cardiology and Functional Genomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany., Krämer C; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, BioQuant, University of Heidelberg, Heidelberg, Germany., Clauder-Münster S; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Perlas E; Epigenetics and Neurobiology Unit, EMBL Rome, Monterotondo, Italy., Backs J; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.; Institute of Experimental Cardiology, University Hospital Heidelberg, Heidelberg, Germany., Gotthardt M; Translational Cardiology and Functional Genomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.; Department of Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany., Dieterich C; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.; Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany., van den Hoogenhof MMG; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.; Institute of Experimental Cardiology, University Hospital Heidelberg, Heidelberg, Germany., Grimm D; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, BioQuant, University of Heidelberg, Heidelberg, Germany.; German Center for Infection Research (DZIF), Partner Site Heidelberg, Heidelberg, Germany., Steinmetz LM; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. Lars.Steinmetz@stanford.edu.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Lars.Steinmetz@stanford.edu.; DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany. Lars.Steinmetz@stanford.edu.; Stanford Genome Technology Center, Palo Alto, CA, USA. Lars.Steinmetz@stanford.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jun 22; Vol. 14 (1), pp. 3714. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1038/s41467-023-39352-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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