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CHARLOTTESVILLE, Va.—By turning some mice into "super-jocks," a team of University of Virginia Health System researchers believes it may have hit upon a way to treat—and perhaps even reverse—neurodegenerative conditions like Parkinson's disease, Alzheimer's disease and Lou Gehrig's disease. The results may even have broader implications for diseases like cancer, diabetes and age-related ailments.
Publishing their findings in the Mitochondria Research Society journal Mitochondrion, which posted the article online in mid-February, the team says that the protein, recombinant-human mitochondrial transcription factor A (rhTFAM), not only successfully entered the DNA of the mice's mitochondria, but also "energized" them, enabling them to run two times longer on their rotating rods than could mice in a control group.
This is important, the researchers says, because many neurodegenerative diseases cause mitochondria to malfunction, and they and other researchers therefore have been focusing on finding ways to repair mitochondria and restore their function. The University of Virginia study suggests that the naturally occurring protein TFAM can be engineered to rapidly pass through cell membranes and target mitochondria.
In addition to testing this theory with mice, the researchers showed that rhTFAM also acts on cultured cells carrying a mitochondrial DNA disease. Furthermore, the study also describes a scalable method of producing the protein in necessary quantities, which is, of course, a critical factor for future discovery, development and commercial efforts.
Although the study's lead author, Dr. James P. Bennett Jr., foresees a day when his team's efforts may help lead to ways to "reverse or delay the progression of various neurodegenerative diseases and other conditions where cell energy production is deficient," he says it is important to focus on just one area for now: neurodegenerative diseases. And, more specifically—for now at least—on Lou Gehrig's disease.
"In the drug development process, you really need to pick one thing to focus on, and then as you show some value for one disease, you can get the FDA to be more amenable to other disease targets," notes Bennett, director of the University of Virginia School of Medicine's Center for the Study of Neurodegenerative Diseases and a professor of neurology and psychiatric research at the school. "It seemed to us that the best place to focus our efforts on—and the place where we were most likely to see success—was in the neurodegenerative area, specifically amyotrophic lateral sclerosis, or ALS, which is Lou Gehrig's disease."
He says that ALS rose to the top of the list fast, in part because it's a disease area he and his colleagues are involved in directly, both in general and with the mitochondrial aspects, and "because it's a kind of high-profile disease, with a lot of sad outcomes and really no cure. That might help to generate interest later from potential partners and funders."
The study was conducted in conjunction with Gencia Corp., a Charlottesville-based biotechnology firm that owns rhTFAM, and which made rhTFAM available to the university under a material transfer agreement. One study author, Francisco R. Portell, has an affiliation with the company, though none of the authors have a financial stake in the company.
As for how soon their research work might see the bedside, that's still up in the air, given how early-stage this work still is, but Bennett says, "In the best of all possible worlds, we could be in the clinics with human testing of a potential therapy for ALS in two to three years."
But timing isn't as important as the excitement that the research generates, and the roads it opens to future studies. As the study's authors noted in the paper, "Much remains to be characterized about the mechanisms underlying our observations, and the therapeutic potential of [TFAM] for treating diseases associated with bioenergetic deficiency is worthy of further investigation. More importantly, our findings show that the mitochondrial genome is no longer an isolated site and can be manipulated from outside the cell with targeted protein transduction technology."
That is critical, they say, because mitochondria are the cellular engines that transform food into fuel, performing their work in the energy-intensive tissue of our brains, retinas, hearts and skeletal muscles. When damaged, mitochondria slow down, stop generating energy effectively and begin to over-produce oxygen free radicals. If produced in excess, oxygen free radicals chemically attack all cell components, including proteins, DNA and lipids in cell membranes.
"In simple terms, an overabundance of these free radicals cause cells to start rusting," Bennett says. "We've shown that the human mitochondrial genome can be manipulated from outside the cell to change expression and increase mitochondrial energy production, and this is arguably the most essential physiological role of the mitochondria."