Study Finds Genome Editing Platform Effective in Targeting Mutant Mitochondrial DNA

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A new study led by a University of Miami Miller School of Medicine investigator has found that a leading-edge genome editing platform can effectively target mutant mitochondrial DNA (mtDNA) in the cells of vulnerable organs and tissues.

“Genetic mutations are largely responsible for mitochondrial disorders that reduce the production of cellular energy in different organs and tissues,” said Carlos T. Moraes, Ph.D., Esther Lichtenstein Professor in Neurology. “This preclinical study could lead to new strategies for addressing currently untreatable mitochondrial disorders.”

Dr. Carlos T. Moraes

Dr. Moraes was the lead author of the study, “Mitochondrial-Targeted Meganuclease: A Novel Platform to Eliminate Mutant mtDNA in Vivo,” published June 1 in the journal Nature Communications. Miller School co-authors were Ugne Zekonyte, Ph.D. candidate; Sandra R. Bacman, Ph.D., associate scientist; and Claudia V. Pereira, Ph.D., postdoctoral associate, Department of Neurology. Scientists from Precision BioSciences Inc., a clinical stage biotechnology company, were also instrumental in developing this new tool.

“Within a cell, the mitochondria will typically have a mixture of mutant and normal or wild-type (WT) mtDNA molecules – a condition called heteroplasmy,” said Dr. Moraes. “Serious disorders can occur when the mutant DNA molecules reach dangerously high levels, compromising the cell’s function. But if mtDNA levels can be reduced through appropriate gene editing therapy, the cell can repopulate the mitochondria with wild-type mtDNA molecules, restoring health to affected tissues and organs.”

For the laboratory study, Dr. Moraes and his team used the ARCUS® genome editing platform developed by Precision BioSciences. When the researchers used an adeno-associated virus (AAV) to deliver the ARCUS platform to adult mice, they found robust elimination of mutant mtDNA in liver and skeletal muscle cells followed by improvement in mitochondrial markers.

Mutant mitochondrial diseases are multi-systemic disorders with a wide range of symptoms, even in patients carrying the same mutation. They can affect any organ or tissue in the body, causing optic atrophy, stroke-like episodes, heart disorders, muscle weakness, and neurodegeneration.  “We are very excited with this early research and the great promise we believe it suggests for using ARCUS editing in patients with mtDNA diseases in the future,” Dr. Moraes said.

Noting the safety and efficacy of the ARCUS gene editing platform in this mouse model, Derek Jantz, Ph.D., co-author of the study and chief scientific officer at Precision BioSciences, said, “We continue to see promising results in pre-clinical studies suggesting that ARCUS could potentially deliver similar results in vivo in human clinical trials. I congratulate Carlos and his team on this research and look forward to further work on this program.”