Old Drug Shows New Promise For Huntington's Disease

The study, led by principal investigator Stephen M. Massa, MD, PhD,a neurologist at SFVAMC, was reported in the August 16, 2005 issue ofProceedings of the National Academy of Sciences.

Huntington's disease is a hereditary, degenerative, andultimately fatal disease of the brain that causes changes inpersonality, progressive loss of memory and cognitive ability, and acharacteristic uncontrolled jerking motion known as Huntington'schorea. There is no known cure or effective treatment. A person whocarries the mutant Huntington's gene may pass it on unknowingly becausethe disease often manifests in early to late middle age after thecarrier's children have already been born.

During the course of the disease, the Huntington's gene causes theproduction of a toxic protein, mutant huntingtin, in neurons (braincells). Eventually the protein kills the neurons, causing the disease'sdegenerative effects.

In Massa's study, Clioquinol appeared to interrupt theproduction of mutant huntingtin.In the first part of his study, Massa and his research team tested theeffect of Clioquinol on neurons in cell culture that contained a formof the mutant Huntington's gene. "We found that not only did cells lookbetter and survive a bit longer when exposed to the drug, but they alsoseemed to make less of the toxic protein," observed Massa, who is alsoa clinical assistant professor of neurology at the University ofCalifornia, San Francisco (UCSF).

Based on the in vitro results, Massa decided to test the drug in vivo,on mice bred to express the toxic huntingtin protein. The mice weregiven approximately 1 milligram of Clioquinol per day in water. Aftereight weeks of treatment, they had accumulated four times less toxicprotein in their brains than control mice given water alone. Theexperimental animals lived 20 percent longer than the control animals,did better on tests of motor coordination, and had less weight loss.

"It's a limited study, in that we used the same drug dose onall the animals as opposed to comparing different doses, but fairlyconvincing," Massa concluded. "Together, the in vitro and in vivoresults suggest that Clioquinol has an effect of decreasing thesymptoms of Huntington's, its pathology, and perhaps even the actualproduction of the toxic protein."

However, he noted, "the drug's mechanism of action remainsunclear." The clearer the mechanism of the drug, he explained, thebetter the chance that researchers might eventually be able to create amedication that is both safe and effective.

Like some other antibiotics, Clioquinol is known to be achelator -- that is, it binds metals in body tissues, particularlycopper and zinc, and removes them when it is excreted. Massa and otherresearchers believe that this chelation effect may interfere withproduction of the mutant huntingtin protein in some way. "But there arestill a couple of explanations we need to rule out," he said.

To that end, Massa's next studies will involve the creation ofan in vitro system in which toxic and non-toxic forms of huntingtin aremade in the same cell. He and his team will then evaluate the effectsof Clioquinol on several phases of protein synthesis within the cell.Massa hopes these experiments will confirm initial indications thatClioquinol preferentially interferes with synthesis of the toxic formof the protein. "Then we can move on to trying to isolate the actualmechanism of the drug," he predicted.

"However," Massa cautioned, "the record of successfully translating drugs from animal to human use is not good."

Clioquinol has shown promise as a potential treatment for Alzheimer'sdisease in recent studies in mice and humans. Apparently throughchelation, it interferes with the creation of beta-amyloid plaque inthe brain, which has been implicated in the progression of Alzheimer'ssymptoms.

Currently, Clioquinol is banned for internal use in manycountries because of its side effects. In Japan in the late 1950s and60s, the drug was found to cause a neurologic condition called subacutemyelo-optico-neuropathy (SMON), with symptoms including visual loss,muscle weakness, and numbness, in several thousand people. However,noted Massa, the doses given in current clinical trials are muchsmaller than were commonly prescribed in Japan. In addition, heexplained, it has been found that vitamin B12, when taken along withthe drug, protects against its potential toxic effects.

Co-authors of the study were Trent Nguyen, PhD, and Aaron Hamby, BS, of SFVAMC and UCSF.

The research was funded by a grant from the U.S Department of Veterans Affairs.