Researchers in Chile have succeeded in keeping the drinking habits of alcoholic rats in check using gene therapy. The treatment mimics a natural mutation common in East Asian people, which lowers their tolerance to alcohol, making them less likely to become alcoholics.
According to the National Institutes of Health, 17.6 million people abuse alcohol or are alcohol dependent in the United States alone. If the gene-therapy technique could be applied to humans, scientists say that it may be a valuable addition to the drugs and behavioral approaches currently used to treat alcoholism.
The gene therapy works in a similar way to a drug currently used to treat alcoholics, which is effective but unpopular with patients, many of whom stop taking it.
“It’s great when innovative approaches are being used for treatment, because we need them,” says George Koob, codirector of the Pearson Center for Alcoholism and Addiction Research, at the Scripps Research Institute. He was not involved in the work in Chile.
The gene therapy, described in the latest issue of the journal Alcohol: Clinical and Experimental Research, curbed the activity in the liver of an enzyme–aldehyde dehydrogenase–that plays a major role in metabolizing alcohol. Nearly a third of East Asians have a natural genetic mutation that has the same effect, so when they drink, their faces turn red, their hearts pound, and they feel sick–all good incentives to go easy on alcohol.
The gene therapy tested by Yedy Israel, a professor of pharmacological and toxicological chemistry at the University of Chile, and his colleagues triggers the same unpleasant response to alcohol in rats.
“It’s a new way of doing an old thing,” Koob says. “I think it’s very clever and very interesting.”
The researchers in Chile started with rats bred for their alcoholic tendencies and offered them unlimited quantities of diluted ethanol–the equivalent of higher-alcohol premium beer–for two months to make them even more dependent. The researchers then cut off the animals’ access to alcohol and injected some of them with a virus containing a gene that inhibits aldehyde dehydrogenase.
Three days later, the researchers implemented a month of daily “happy hours,” letting the rats drink as much as they wanted. In an hour, each of the animals put away the equivalent, in human terms, of about seven premium beers–10 times more alcohol than what was put away by alcoholic animals that hadn’t been through the two-month dependency regimen.
During the first happy hour, rats that were given gene therapy “didn’t realize they were going to feel bad, and they drank a tremendous amount,” Israel says. Afterward, “the animals clearly didn’t look comfortable.” Those rats then markedly reduced their alcohol consumption on subsequent days. Over the course of the happy hours, they drank half as much, on average, as the untreated animals. The effect lasted throughout the monthlong study.
Israel and his colleagues are now working on ways of delivering gene therapies that last for years or even a lifetime, in the hope of developing long-lasting treatments for alcoholism. Most of the medications available now need to be taken at least once a day, and many alcoholics don’t comply with the routine. A longer-lasting drug is likely to be more successful, Israel says.
Two of the three existing drug treatments approved for alcoholism by the Food and Drug Administration–naltrexone and acamprosate–limit the craving for alcohol. The other treatment–disulfiram–works in a similar way to Israel’s gene therapy: by making patients sick if they drink. The trace of alcohol in mouthwash is enough to trigger a reaction, and most alcoholics “really dislike this medication,” says Carolyn Drazinic, an assistant professor in the Department of Psychiatry and the Department of Genetics and Developmental Biology at the University of Connecticut. She was not involved in the gene-therapy research.
“All of these drugs,” Israel says, “really require patients’ compliance with their medication, which is rare.”
Drazinic says, though, that a lifelong treatment that makes someone sick after a whisper of alcohol might not have too many takers. “There may be a lot of patients who would refuse something like this, if they’ve ever experienced a disulfiram reaction,” she says. Drazinic believes that a more popular option might be a treatment that doesn’t last a lifetime, but long enough not to be a daily hassle.
That, Koob says, would be better than “someone sitting there with a baseball bat telling you to take your Antabuse [the trade name for disulfiram] with your Wheaties.”
Robert Swift, a professor of psychiatry and human behavior and the associate director of
Brown University’s Center for Alcohol and Addiction Studies, says that the gene-therapy approach “is a very interesting technique, but it’s not ready for prime time.”
“There are a lot of medications that reduce drinking in animals but may not be as effective in humans,” he says. “The question is, can you really make enough difference in the enzymes that humans will reduce their drinking?”
Gene therapy is risky, and if it’s ever used to treat alcoholism in humans, it should be a last-ditch option for hardcore alcoholics, Swift says. However, those patients are often suffering from liver damage, and “if someone’s got damaged liver cells, you’ve got a greater risk of complications from genetic treatment.”
Israel’s gene-therapy approach is “perfectly logical,” says Raymond White, director of the University of California, San Francisco’s Ernest Gallo Clinic and Research Center, where scientists study the biological basis of alcohol and substance abuse. But White adds that he’d be quite surprised “if this became a real therapy.”
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