Gene therapy curbs nicotine addiction in mice

Forget patches: gene therapy could suppress cigarette cravings by preventing the brain from receiving nicotine. The treatment is effective in mice, but with gene therapy still not fully tested in people, human trials and treatments are a long way off.

For drug users who really can't quit, vaccination might one day be an option, and several groups have attempted to develop such treatments.

But nicotine vaccines have mostly flopped. This is because nicotine is a very small molecule, so the immune system has difficulty recognising the drug and making antibodies that bind it. Physicians can inject antibodies directly into a patient, but this treatment quickly becomes expensive because the antibodies don't last long.

Ronald Crystal of Weill Cornell Medical College in New York and his team decided to bypass that problem by putting the gene for a nicotine antibody right into the body.

They selected the strongest antibody against nicotine from a mouse and isolated the gene that produced it. They then placed this gene into a carrier called adeno-associated virus (AAV), which is widely used for gene therapy.

When the researchers injected the virus and its cargo into nicotine-addicted mice, the rodents' livers took up the virus, began making antibodies and pumped them into the bloodstream. The researchers injected two cigarettes' worth of nicotine into AAV-infected mice. The antibodies were able to bind 83 per cent of the drug before it reached the brain.

Different response

Without their drug, the mice's behaviour changed. Nicotine usually causes mice to "chill out", Crystal says, but the researchers found that the treated mice stayed active and their heart rates stayed normal when they received nicotine.

Eighteen weeks later, the mice's livers were still making the antibody, suggesting that the therapy might render nicotine useless to smokers for long periods.

Jude Samulski at the University of North Carolina at Chapel Hill, who was part of the team that developed AAV as a gene therapy vector, says he's "ecstatic" that the vector has come so far. He calls the research "a gorgeous piece of work" that has "leapfrogged" the difficulties faced by vaccines.

But he has doubts about whether gene therapy is well-tested enough to be used to treat nicotine addiction. So far, AAV has been clinically tested in people with HIV or terminal cancer where potential benefits far outweigh the risks. "It's ahead of its time. In 10 years there may be enough safety data," he says. "Quitting smoking might be easier."

Thomas Kosten of Baylor College of Medicine in Houston, Texas, shares those doubts. Unlike patients with terminal diseases, "smokers are normal people with decades of life ahead of them", he says, and gene therapy can be risky. He believes that a better, safer vaccine will be developed by the time this system passes safety tests.

Crystal agrees that human studies are many years away: the next step is to test the vector in primates. In the meantime, he says, the same model could be useful to develop gene therapies for methamphetamine, cocaine or any addictive drug.

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.3003611

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