Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 40, Pages 14392-14397Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0502896102
Keywords
gene therapy; mitochondria
Categories
Funding
- NEI NIH HHS [R01 EY010804, P30 EY014801, EY10804, R01 EY010804-08, EY014801, R01 EY010804-07] Funding Source: Medline
- NINDS NIH HHS [NS41777, R56 NS041777, R01 NS041777] Funding Source: Medline
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Frequently, mtDNA with pathogenic mutations coexist with wildtype genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. These mice have two mtDNA haplotypes, of which only one contains an ApaLI site. After transfection of cultured hepatocytes with mitochondrially targeted ApaLI, we found a rapid, directional, and complete shift in mtDNA heteroplasmy (2-6 h). We tested the efficacy of this approach in vivo, by using recombinant viral vectors expressing the mitochondrially targeted ApaLI. We observed a significant shift in mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses. This strategy could prevent disease onset or reverse clinical symptoms in patients harboring certain heteroplasmic pathogenic mutations in mtDNA.
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