In vivo delivery of a novel tandem mtZFN architecture via AAV significantly reduced the mtDNA mutation load by up to 40% in skeletal and cardiac muscle of a murine model.
Does in vivo mitochondrial gene therapy using mtZFNs reduce mutation load in a murine model harboring a pathogenic mtDNA mutation?
In vivo mitochondrial gene therapy using a novel mtZFN architecture effectively reduces mtDNA mutation load and provides molecular phenotypic rescue in a murine model, highlighting its potential for treating mitochondrial diseases.
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.
Nash et al. (Wed,) conducted a other in Mitochondrial disease (m.5024C>T mutation). Tandem mtZFN (MTM25-T2A-WTM1) via AAV vs. Vehicle or separate mtZFN monomers was evaluated on Heteroplasmy shift (reduction in mutation load). In vivo delivery of a novel tandem mtZFN architecture via AAV significantly reduced the mtDNA mutation load by up to 40% in skeletal and cardiac muscle of a murine model.