Research ArticleAddiction

AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation

Science Translational Medicine  27 Jun 2012:
Vol. 4, Issue 140, pp. 140ra87
DOI: 10.1126/scitranslmed.3003611

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Extinguishing Addiction

Those who smoke and try to quit have variously described their feelings as a never-ending hunger, terror, immense panic, rage, and the loss of a loved one—reactions that stem from nicotine addiction and withdrawal. Given cigarette smoke’s destructive effects on health and cost to society, a means of overcoming such addiction would be enormously beneficial. For most smokers, current antismoking therapies fail to work. One newer idea is an anti-nicotine vaccine; in this approach, nicotine (coupled to a larger molecule) is administered, generating an immune response. The resulting anti-nicotine antibodies bind the nicotine from cigarette smoke in the blood, intercepting the drug before it affects reward centers in the brain. In disappointing clinical trials, however, such vaccines result in variable antibody titers and have only limited success in halting smoking, with best results seen in people with the strongest antibody response. Hicks et al. now describe a different tactic to get to the same end; they use gene transfer to attain persistent, high levels of anti-nicotine antibodies in smokers’ blood.

The researchers constructed an adeno-associated virus–based vector that expressed a high-affinity anti-nicotine monoclonal antibody. Mice injected with a single dose of this vector made high antibody titers (which were in 40-fold molar excess over the nicotine concentrations seen in people who smoke continuously), which remained high for at least 18 weeks. When these mice were injected with nicotine, the antibodies effectively sequestered this compound in the blood: nicotine concentrations in the brain were only 15% of those in brains of mice that did not express the antibodies. Furthermore, the usual nicotine-induced changes in blood pressure, heart rate, and locomotor activity were abolished or greatly reduced in mice that expressed the anti-nicotine antibodies.

Further work will be needed to test this vector in a rodent model trained to self-administer nicotine, because the mice in this study were not addicted to the drug. Successful results from such a test would then support investigating this approach in clinical trials.