Advances in Gene Editing and Delivery Offer Promise for People Living with Mitochondrial Diseases
There is strength in numbers — or at least the right proportion. A new study from University of Miami Miller School of Medicine researchers demonstrates an ability to target and reduce debilitating high levels of mutant mitochondrial DNA in heart and other muscle tissue to an extent — so far in mice — that could be curative.
The findings offer hope to people living with relatively rare mitochondrial diseases, such as Kearns-Sayre syndrome, progressive external ophthalmoplegia, myoclonus epilepsy with ragged-red fibers, and Pearson’s syndrome.
The DNA inside mitochondria — the “power plants” that generate energy in most cells and allow proper functioning — is present in multiple copies, and mutations cause diseases only when present in the vast majority of these molecules. People with high levels of mutated mitochondrial DNA (mtDNA) can experience muscle weakness, developmental delays, seizures, and other serious adverse effects.
For years, researchers have searched for an effective way to reduce the high number of mutant mtDNA molecules in critical organs, like the heart, and in skeletal muscle.
In a new study published in Nature Medicine, Carlos T. Moraes, Ph.D., professor of neurology and cell biology, and the Esther Lichtenstein Chair in Neurology, lead author Sandra R. Bacman, Ph.D., associate scientist in the Department of Neurology, and their colleagues offer a promising way to accomplish precisely that.
“We can reduce the levels of mutant mtDNA in cells that have a mix of normal and mutant mtDNA,” said Dr. Moraes. “This change has the potential to eliminate clinical manifestations.”
Building on previous success in cell cultures, Dr. Moraes and team analyzed mice engineered with a specific genetic mutation that reflects certain mitochondrial diseases in humans. Following a single intramuscular injection of mitochondrial transcription activator-like effector nucleases (MitoTALENs), they observed a rapid decrease in the ratio of mutant-to-normal mtDNA.
The beneficial effect was maintained over time, analyzed up to 24 weeks after the single injection, suggesting a sustained clinical benefit could be possible.
Interestingly, the strategy does not eliminate all mutant mtDNA. Rather, it lowers it to a mutant-to-normal ratio where cells can once again produce energy and function efficiently. Total elimination of the mutant mtDNA is not necessary to see clinical improvement, the researchers noted.
Collaboration made the current research possible.
“Our group has been working on this problem for many years,” Dr. Moraes said. “We used several UM shared facilities for our work, including cell sorting and imaging. We also used shared facilities from other institutions to provide recombinant viral preparations. In addition, the mouse model provided by our collaborators at the Max Planck Institute in Cologne, Germany, was critical to test this approach in vivo.
“The approach appears safe in mice, and we would like to move it into humans. Of course, the delivery of genes to several tissues is still a challenge.”
Drs. Bacman, Moraes, and colleagues hope the current findings will translate into a clinical trial next.
“If we and others can improve the delivery of mitoTALEN to affected tissue, this approach can be curative,” said Dr. Moraes.