A drug that flopped as a cholesterol-fighter may be a powerful therapy against metabolic disorders that have so far defied effective treatment, concludes a study led by Children's Hospital of Philadelphia.
Although the study was conducted on mice, it sheds light on human diseases rooted in the mitochondria - the so-called powerhouses of the cell. The drug, probucol, not only prevented but reversed otherwise fatal kidney damage in mice bred to mimic a human mitochondrial disease.
"We were just dazzled that it really did work," said study leader Marni Falk, a pediatrician in the Mitochondrial-Genetics Disease Clinic at Children's. "There are no effective cures for mitochondrial diseases, even in animals. So these striking results in mice may suggest a novel therapy for humans."
Much research remains to be done before probucol could be tested in humans, Falk said. Still, her 14-member team, which includes scientists from the University of Pennsylvania and UCLA, has clearly shown it is possible to repair the bogglingly complex cellular signaling that goes awry in mitochondrial disorders. The study was designed by and built on many years of work by the senior author, Penn geneticist David L. Gasser.
"We did some screening studies . . . to see what biological-signaling pathways we were changing," Falk said. "Many were changed."
Mitochondria - self-replicating structures with their own DNA - evolved from bacteria that found a permanent home in primordial cells by enabling those cells to convert oxygen into energy.
Almost every cell in the human body now has hundreds or thousands of mitochondria that use food and oxygen to generate and regulate the energy that keeps the body alive.
Even though the origins of mitochondria go back more than a billion years, the first disease-causing mutations in mitochondrial DNA were identified just 22 years ago. The discoverer, research pioneer Douglas C. Wallace, joined Children's last summer to establish the Center for Mitochondrial and Epigenomic Medicine.
Since Wallace's 1988 breakthrough, hundreds of mutations have been pinpointed, and the associated mitochondrial diseases - causing symptoms as diverse as weakness, strokes, and deafness - are estimated to affect at least one in 5,000 people. That is more prevalent than commonly thought, yet not surprising, considering the energy demands of such vulnerable organs as the brain and muscles.
Because medical science has a limited understanding of the cellular mechanics of mitochondria, developing therapies has been difficult.
"Therapy for mitochondrial diseases is woefully inadequate," Columbia University researchers wrote in a 2004 article in the New England Journal of Medicine.
Treatments, they said, have been aimed at palliation - relieving symptoms without addressing the cause - or giving vitamins, enzymes, and other substances necessary to metabolism.
The Children's study, for example, modeled an inherited human mitochondrial disease that prevents production of a metabolite called ubiquinone. Also known as coenzyme Q10 (CoQ10), it has become a popular dietary supplement.
CoQ10 is a vitaminlike substance that ferries electrons - electrical energy - within the cell. CoQ10 deficiency has been found in numerous mitochondrial diseases that cause muscle weakness and wasting, yet treating the deficiency with CoQ10 pills is as ineffective as pouring water on a drought-hardened field.
"Simply providing a missing metabolite frequently has no clinical efficacy," Falk and colleagues wrote in their paper, published online last month in the journal EMBO Molecular Medicine. "For example, while some children born with defective CoQ biosynthesis respond to CoQ10 supplementation, many do not."
Why try probucol?
In the late 1980s, Dow Chemical gave up developing it as a heart-disease treatment for the U.S. market because it reduced both good and bad types of cholesterol. But the compound continued to intrigue some researchers because it also reduces oxidation - the reactive oxygen damage that contributes to many disease processes.
Falk's group was intrigued by a German study, published in 1999, that found probucol's anti-lipid and anti-oxidation properties arrested kidney damage in mice with a kidney disease.
In the new study, mice that ate special chow laced with probucol were compared with those who consumed CoQ10 or went untreated. Depending on whether probucol was given before or after kidney damage set in, the mice stayed healthy or their kidney function went back to normal.
Figuring out why required sophisticated molecular tests.
It turned out that the drug was changing signaling pathways, particularly one that restored CoQ10 production.
Falk's heartening conclusion: Mitochondrial defects are "a complex group of disorders, but it's not hopeless."