Scientists have engineered an enzyme that breaks down nicotine in the bloodstream before it can reach the brain, according to a report published in the journal Science Advances.
In tests on lab rats, 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.
The study’s principal investigator, Olivier George, said: ‘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.’
Nicotine dependence is what keeps tobacco smokers smoking despite all the harm it does to their health. Researchers estimate that about 60 per cent of the people who try cigarettes end up as daily smokers, and about 75 per cent of daily smokers relapse after quitting.
Reversing nicotine dependence by preventing the nicotine in tobacco smoke from reaching the brain has long been considered a promising strategy. However, prior efforts have not yielded drugs that reduce blood levels of nicotine enough to be effective.
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 optimise its potency, its staying time in the blood, and other pharmacological properties.
During one set of experiments, lab rats spent 21 hours of every day, for 12 days, in a chamber where they could press a lever to give themselves an intravenous infusion of nicotine. In this way they learned to self-administer nicotine, and became dependent on it. After the 12 days they were given access to nicotine only every 48 hours, which led them to experience withdrawal symptoms between access periods, and to escalate their intake.
Animals treated with the highest dose of NicA2-J1 (10 mg/kg) continued to self-administer nicotine when they could, but showed very low blood levels of the molecule compared to controls that did not receive the enzyme. Signs of nicotine withdrawal, such as susceptibility to pain and aggressive behaviours, were correspondingly reduced during the no-access periods, compared to untreated controls.
With such promising results in preclinical tests, the researchers hope to now take NicA2-J1 into clinical trials in humans.