Scientists have developed a new approach to eliminate mutated DNA inside mitochondria that they say could be used to treat a variety of mitochondrial diseases, including the degenerative eye disease Leber hereditary optic neuropathy (LHON)—they have, for the first time, used TALENs to edit mitochondrial genes.
Investigators at the University of Miami Miller School of Medicine explored transcription activator-like (TAL) effectors while looking for new strategies to repair mitochondrial gene defects—more specifically, TAL effector nucleases (TALENs), which can be used for gene editing. The investigators used cells in the lab to design mitochondrial-targeted TALENS (mitoTALENs) to bind and cut mitochondrial DNA that had a specific mutation in the gene Complex I, which causes LHON. The scientists then tested whether the mitoTALENs eliminated the mutant mtDNA. Their analysis revealed a temporary drop in cells’ total mtDNA, which was due to a reduction in mutant mtDNA.
“Once the mitoTALENs bound and cut the DNA at the specified target, the mutant mtDNA was degraded,” said Carlos T. Moraes, Ph.D., a professor of neurology and cell biology at the University of Miami Miller School of Medicine and principal investigator of the study. “The drop in total mtDNA stimulated the cells to increase their mtDNA by replicating the unaffected molecules. Two weeks later, mtDNA levels had returned to normal. But since the mutant mtDNA was destroyed, the cells had mostly normal mtDNA.”
Reducing but not necessarily eliminating all mutant mtDNA from a person’s cells would be sufficient to treat many mitochondrial diseases, Dr. Moraes noted, as mutant mtDNA typically does not cause signs of disease until it makes up 80% or more of the total mtDNA in a cell.
The scientists’ next step will be to test the approach in animals.
The research, published online August 4 in Nature Medicine with title “Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs,” was funded by the National Eye Institute (NEI), a part of the NIH.