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

  1. Grosch, Markus ORCID logo
  2. Schraft, Laura ORCID logo
  3. Chan, Adrian
  4. Küchenhoff, Leonie ORCID logo
  5. Rapti, Kleopatra
  6. Ferreira, Anne-Maud
  7. Kornienko, Julia ORCID logo
  8. Li, Shengdi
  9. Radke, Michael ORCID logo
  10. Krämer, Chiara
  11. Clauder-Münster, Sandra
  12. Perlas, Emerald
  13. Backs, Johannes
  14. Gotthardt, Michael ORCID logo
  15. Dieterich, Christoph ORCID logo
  16. van den Hoogenhof, Maarten ORCID logo
  17. Grimm, Dirk ORCID logo
  18. Steinmetz, Lars ORCID logo

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WeightNameValue
1000 Titel
  • Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy
1000 Autor/in
  1. Grosch, Markus |
  2. Schraft, Laura |
  3. Chan, Adrian |
  4. Küchenhoff, Leonie |
  5. Rapti, Kleopatra |
  6. Ferreira, Anne-Maud |
  7. Kornienko, Julia |
  8. Li, Shengdi |
  9. Radke, Michael |
  10. Krämer, Chiara |
  11. Clauder-Münster, Sandra |
  12. Perlas, Emerald |
  13. Backs, Johannes |
  14. Gotthardt, Michael |
  15. Dieterich, Christoph |
  16. van den Hoogenhof, Maarten |
  17. Grimm, Dirk |
  18. Steinmetz, Lars |
1000 Erscheinungsjahr 2023
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2023-06-22
1000 Erschienen in
1000 Quellenangabe
  • 14(1):3714
1000 Copyrightjahr
  • 2023
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1038/s41467-023-39352-1 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10287752/ |
1000 Ergänzendes Material
  • https://www.nature.com/articles/s41467-023-39352-1#Sec32 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
lokal CRIDPR-Cas systems
lokal Cardiomyopathies
lokal Medical genetics
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. http://orcid.org/0000-0001-9016-8920|http://orcid.org/0009-0005-4504-8926|https://frl.publisso.de/adhoc/uri/Q2hhbiwgQWRyaWFu|http://orcid.org/0000-0002-3715-4551|https://frl.publisso.de/adhoc/uri/UmFwdGksIEtsZW9wYXRyYQ==|https://frl.publisso.de/adhoc/uri/RmVycmVpcmEsIEFubmUtTWF1ZA==|http://orcid.org/0000-0002-7876-230X|https://frl.publisso.de/adhoc/uri/TGksIFNoZW5nZGk=|http://orcid.org/0000-0003-0112-9917|https://frl.publisso.de/adhoc/uri/S3LDpG1lciwgQ2hpYXJh|https://frl.publisso.de/adhoc/uri/Q2xhdWRlci1Nw7xuc3RlciwgU2FuZHJh|https://frl.publisso.de/adhoc/uri/UGVybGFzLCBFbWVyYWxk|https://frl.publisso.de/adhoc/uri/QmFja3MsIEpvaGFubmVz|http://orcid.org/0000-0003-1788-3172|http://orcid.org/0000-0001-9468-6311|http://orcid.org/0000-0003-2768-3457|http://orcid.org/0000-0001-6227-5665|http://orcid.org/0000-0002-3962-2865
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1000 Erstellt am 2023-10-19T13:39:39.465+0200
1000 Erstellt von 337
1000 beschreibt frl:6462081
1000 Bearbeitet von 317
1000 Zuletzt bearbeitet Tue Oct 24 08:33:55 CEST 2023
1000 Objekt bearb. Tue Oct 24 08:33:33 CEST 2023
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  1. oai:frl.publisso.de:frl:6462081 |
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