Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture
Abstract Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected m...
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Springer Nature
2025-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00231-5 |
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| author | Pavel A Nash Keira M Turner Christopher A Powell Lindsey Van Haute Pedro Silva-Pinheiro Felix Bubeck Ellen Wiedtke Eloïse Marques Dylan G Ryan Dirk Grimm Payam A Gammage Michal Minczuk |
| author_facet | Pavel A Nash Keira M Turner Christopher A Powell Lindsey Van Haute Pedro Silva-Pinheiro Felix Bubeck Ellen Wiedtke Eloïse Marques Dylan G Ryan Dirk Grimm Payam A Gammage Michal Minczuk |
| author_sort | Pavel A Nash |
| collection | DOAJ |
| description | Abstract Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments. |
| format | Article |
| id | doaj-art-0ea527046bec41c6b2e7dd9f4a54ca99 |
| institution | OA Journals |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0ea527046bec41c6b2e7dd9f4a54ca992025-08-20T02:06:35ZengSpringer NatureEMBO Molecular Medicine1757-46842025-04-011761222123710.1038/s44321-025-00231-5Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecturePavel A Nash0Keira M Turner1Christopher A Powell2Lindsey Van Haute3Pedro Silva-Pinheiro4Felix Bubeck5Ellen Wiedtke6Eloïse Marques7Dylan G Ryan8Dirk Grimm9Payam A Gammage10Michal Minczuk11MRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeDepartment of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, Heidelberg UniversityDepartment of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, Heidelberg UniversityMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeDepartment of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, Heidelberg UniversityMRC Mitochondrial Biology Unit, University of CambridgeMRC Mitochondrial Biology Unit, University of CambridgeAbstract Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.https://doi.org/10.1038/s44321-025-00231-5Gene TherapyZinc Finger Nuclease (mtZFN)Adeno-Associated Viruses (AAV)mtDNA Heteroplasmy ModificationSkeletal Muscle |
| spellingShingle | Pavel A Nash Keira M Turner Christopher A Powell Lindsey Van Haute Pedro Silva-Pinheiro Felix Bubeck Ellen Wiedtke Eloïse Marques Dylan G Ryan Dirk Grimm Payam A Gammage Michal Minczuk Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture EMBO Molecular Medicine Gene Therapy Zinc Finger Nuclease (mtZFN) Adeno-Associated Viruses (AAV) mtDNA Heteroplasmy Modification Skeletal Muscle |
| title | Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |
| title_full | Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |
| title_fullStr | Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |
| title_full_unstemmed | Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |
| title_short | Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |
| title_sort | clinically translatable mitochondrial gene therapy in muscle using tandem mtzfn architecture |
| topic | Gene Therapy Zinc Finger Nuclease (mtZFN) Adeno-Associated Viruses (AAV) mtDNA Heteroplasmy Modification Skeletal Muscle |
| url | https://doi.org/10.1038/s44321-025-00231-5 |
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