Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture
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 mitochondr...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
9 April 2025
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| In: |
EMBO molecular medicine
Year: 2025, Volume: 17, Issue: 6, Pages: 1222-1237 |
| ISSN: | 1757-4684 |
| DOI: | 10.1038/s44321-025-00231-5 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44321-025-00231-5
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| Author Notes: | 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 |
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| 245 | 1 | 0 | |a Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture |c 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 |
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| 520 | |a 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. | ||
| 650 | 4 | |a Adeno-Associated Viruses (AAV) | |
| 650 | 4 | |a Gene Therapy | |
| 650 | 4 | |a mtDNA Heteroplasmy Modification | |
| 650 | 4 | |a Skeletal Muscle | |
| 650 | 4 | |a Zinc Finger Nuclease (mtZFN) | |
| 700 | 1 | |a Turner, Keira M. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Powell, Christopher A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Van Haute, Lindsey |e VerfasserIn |4 aut | |
| 700 | 1 | |a Silva-Pinheiro, Pedro |e VerfasserIn |4 aut | |
| 700 | 1 | |a Bubeck, Felix |d 1992- |e VerfasserIn |0 (DE-588)1172685525 |0 (DE-627)104131955X |0 (DE-576)514732695 |4 aut | |
| 700 | 1 | |a Wiedtke, Ellen |e VerfasserIn |0 (DE-588)1071738372 |0 (DE-627)826301347 |0 (DE-576)433285206 |4 aut | |
| 700 | 1 | |a Marques, Eloïse |e VerfasserIn |4 aut | |
| 700 | 1 | |a Ryan, Dylan G. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Grimm, Dirk |e VerfasserIn |0 (DE-588)1016476671 |0 (DE-627)70553376X |0 (DE-576)352260645 |4 aut | |
| 700 | 1 | |a Gammage, Payam A. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Minczuk, Michal |e VerfasserIn |4 aut | |
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