Scientists from Weill Cornell Medical College have developed what they hope will turn into a novel anti-addiction strategy. In mice, they were able to prevent the effects of nicotine by treating the animals with an anti-nicotine antibody – administered via gene therapy.

In regular vaccines, such as for measles, mumps or influenza, the vaccine consists of an antigen. "You administer that to the patients, and their own immune system responds," Ronald Crystal told BioWorld Today. Crystal is chairman and professor of genetic medicine at Weill Cornell Medical College and the senior author of the paper describing the approach, which appeared in the June 28, 2012, issue of Science Translational Medicine.

Nicotine, however, does not stimulate the immune system by itself. It can be made to do so, to a degree, by tethering it to a larger molecule – a so-called hapten – that makes nicotine visible to the immune system. But several vaccines, most recently Nabi Pharmaceuticals Inc.'s NicVAX, have failed in the clinic. (See BioWorld Today, July 19, 2011.)

Apparently, the immune system still has to squint a bit too much to make the approach clinically useful. Even coupled to a hapten, nicotine is unable to reliably stimulate an immune response that prevents enough nicotine from reaching the brain to prevent its high.

Another possibility is to make monoclonal antibodies and administer them for reproducibly higher doses. But Crystal succinctly summed up the sticking point of that approach. "Nicotine is a chronic addiction," he said. "Antibodies last at most three to four weeks." To a healthy 30-year-old, coming in monthly for decades of antibody treatment is not an attractive proposition – nor is it financially a realistic option at current antibody prices.

So Crystal and his team decided to deliver such an antibody via gene therapy. They injected mice with a single dose of engineered nicotine antibody, delivered in an adeno-associated virus vector.

The antibody prevented most of a nicotine dose delivered via intravenous injection from entering the brain. Brain levels of animals who had received the antibody gene were only 15 percent of those of untreated controls. Antibody levels remained high for at least 18 weeks, which is as long as the scientists looked.

That lower dose was enough to prevent the behavioral and physiological effects of the drug. "Much like when humans smoke a cigarette, when mice get nicotine, they chill out a little – their heart rate goes down; they move around a little less." But treated mice showed none of those effects. "It's like you're giving water to the mice. Their brain never sees the nicotine," Crystal said.

Gene therapy is now, if not exactly the newest blockbuster, then certainly a lively arm of clinical research that can point to several successes in treating patients with serious diseases. (See BioWorld Today, Dec. 23, 2009, and Aug. 25, 2011.)

But some queasiness at treating addiction with something as permanent as gene therapy is likely to remain. The early days of gene therapy were marked by several spectacular fatalities, such as boys who were cured of immune deficiency only to develop leukemia. Perhaps most tragic was the case of Jesse Gelsinger, who died at age 18 after participating in a clinical trial to cure his partial ornithine transcarbamylase deficiency. (See BioWorld Today, Oct. 14, 1999, and Jan. 16, 2003.)

Crystal is one of the pioneers of gene therapy, being the leader of the first group to ever to test gene therapy in humans, for cystic fibrosis in 1993. (That trial was not successful. The human lung, Crystal wryly noted, evolved very efficiently to protect itself against viruses. . . . "We could cure the disease for about a week" before the immune system destroyed the viral vector, and the therapeutic gene along with it.)

Crystal noted that the viral vector his team used in their experiments, adeno-associated virus, does not integrate into the host genome, making the insertional mutagenesis that cropped up in one immunodeficiency trial a nonissue.

And although there is no such thing as a risk-free medical intervention, "contrast that with the devastating effects of smoking. . . . It causes chronic obstructive pulmonary disorder, the third leading killer in our country, for which there is no drug that impacts mortality. It causes lung cancer, which is the deadliest cancer overall."

Given that risk-benefit ratio, to Crystal, "the main question is can we scale this up" and deliver enough antibody to keep nicotine from crossing into the brain in larger animals? Crystal and his group intend to test that question in larger animals – first rats and then primates. But safety, he said, "is not the major issue."