Engineered enzyme eliminates nicotine addiction in preclinical tests

Scientists at Scripps Research have successfully tested a potential new smoking-cessation treatment in rodents.

In a study published online in Science Advances on Oct. 17, 2018, the scientists gave nicotine-dependent rats an engineered enzyme that breaks down nicotine in the bloodstream before it can reach the brain. Treatment quickly reduced the animals' motivation to take nicotine, reversed their signs of nicotine dependence, and kept them from relapsing when they were given access to nicotine again.

"This is a very exciting approach because it can reduce nicotine dependence without inducing cravings and other severe withdrawal symptoms, and it works in the bloodstream, not the brain, so its side effects should be minimal," says principal investigator Olivier George, Ph.D., associate professor at Scripps Research.

Nicotine dependence is what keeps tobacco smokers smoking despite all the harm it does to their health. Researchers estimate that about 60 percent of the people who try cigarettes end up as daily smokers-and about 75 percent of daily smokers relapse after quitting.

The enzyme tested in this study, NicA2-J1, is a version of a natural enzyme produced by the bacterium Pseudomonas putida. It was modified-to optimize its potency, its staying time in the blood, and other pharmacological properties-by the laboratory of Kim Janda, Ph.D., the Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research. Studies published in the past several years by Janda and colleagues have shown that NicA2-J1 strongly reduces blood levels of nicotine in rodents, and it is effective in a simple rat model of nicotine dependency.

For the new study, the researchers tested the enzyme in more sophisticated animal models, developed in George's laboratory, which better mimic human smokers' addiction to nicotine.