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8.06.2013

Breakthrough DNA Study Opens Door to New Treatments for Mitochondrial Diseases

A groundbreaking cellular genetics study led by Carlos T. Moraes, Ph.D., professor of neurology and cell biology, opens the door to potential new treatments for mitochondrial diseases that affect the nerves, muscles and vital organs.

In the new study, published in the August 4 edition of Nature Medicine, Moraes outlines how the research team was able to eliminate a mutant form of mitochondrial DNA in the cells of two patients with hereditary genetic disorders. Found throughout the human body, except in red blood cells, mitochondria are energy-producing organelles that convert food molecules into the chemical energy currency that cells use to power their functions.

“Many patients with mitochondrial diseases have both normal and mutated mitochondrial DNA (mtDNA),” said Moraes. “We found a way to destroy the mutated one without affecting the normal mtDNA.”

The Miller School researchers used artificial enzymes called transcription activator-like effector nucleases (TALENs) to bind and cut DNA strands in the mitochondria at specific locations, a technique called genome editing. In both types of mtDNA mutations, the researchers were able to dramatically lower the levels of the mutant mtDNA, restoring the cell to its normal bioenergetic state.

The study, “Specific elimination of mutant mitochondrial genomes in patient–derived cells by mitoTALENs,” was published with the Miller School’s Department of Neurology, including co-first authors Siôn L. Williams, Ph.D., research assistant professor, and associate scientist Sandra R. Bacman, Ph.D. Postdoctoral associates Milena Pinto, Ph.D., and Susana Peralta, Ph.D., also contributed.

An estimated 4,000 children are born annually in the U.S. with a type of mitochondrial disease, which can also affect adolescents and older adults. These diseases, which can take many forms, include Leber’s hereditary optic neuropathy (LHON), which leads to vision loss, muscle disorders and several syndromes that affect the brain. The Miller School study focused on cells from one patient with LHON and dystonia and another with a severe multiorgan syndrome affecting brain and muscle.

While not all mitochondrial diseases are caused by mutations in the mtDNA, mitoTALEN-based therapies hold the potential for helping a large fraction of this group of patients, according to Moraes. That’s because when a mutation in the mtDNA occurs, most of the body’s cells have a mix of normal and mutated mtDNA. Unless the mutated mtDNA rises above a certain threshold – such as 80 percent of the combined mtDNA – medical problems are unlikely to occur. Therefore, treatments that reduce the mutated mtDNA below that threshold have the potential to treat the patient’s genetic-related condition. Changing the balance of mutant to normal mtDNA through gene editing tools may require a single procedure. This contrasts with conventional gene replacement therapy, which requires that a corrected gene be expressed for the life of the patient, Moraes added.

“Although further studies are needed, lowering the mutant mtDNA should be sufficient to produce lasting changes in the mitochondria,” Moraes said. “In fact, it is reasonable to expect that a permanent correction of the mitochondrial DNA might be achieved after one or a small number of administrations of mitoTALEN, either as genetic or protein agents.”

Moraes and his research team have done extensive prior studies on cellular disorders, including mutations of the DNA in the nucleus as well as the mitochondria.

The research was supported primarily by the National Eye Institute (EY010804), with contributions from the National Institute on Aging (AG036871), the National Institute of Neurological Disorders and Stroke (NS079965), the Muscular Dystrophy Association and the JDM Fund for Mitocondrial Research.

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