A shot in the arm for smokers

Weill Cornell research team develops vaccine to combat nicotine addiction

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NEW YORK—Some of the latest research from Weill CornellMedical College might result in new hope for smokers who are trying to quit. Ateam of researchers recently announced the successful development and testingin mice of a vaccine to treat nicotine addiction. The research was publishedrecently in Science TranslationalMedicine.
"The problem for nicotine addiction and all addictions isthat the addictive molecules are small, and our immune system doesn't seethem," says Dr. Ronald G. Crystal, chairman and professor of Genetic Medicineat Weill Cornell. "And so there have been many attempts to try to developvaccines by evoking active immunity against nicotine by attaching nicotine toanother molecule and hoping the immune system will see it and developantibodies. The problem is that nicotine is not immunogenic, and so the immunesystem doesn't see it, so it's very hard to develop high levels of activeantibodies against nicotine."
The two main types of vaccines, active and passive, vary intheir approaches. Active vaccines—those used for the prevention of polio andthe mumps—introduces a small amount of the virus or disease in question to apatient's immune system, prompting it to develop a lifetime immune response tothe malady in question. Passive vaccines work by delivering ready-madeantibodies in order to generate an immune response. However, nicotine moleculesare too small to be recognized by the immune system, which eliminates an activevaccine as an option, and previous attempts at vaccines that deliver nicotineantibodies have failed as they only last a few weeks at the most.
The new vaccine from the team at Weill Cornell, however, isa third kind, a genetic vaccine, one that was originally tested on mice as atreatment for certain ocular diseases and tumor types. The vaccine has servedto protect the mice over their lifetimes by using the liver to continuouslyproduce monoclonal antibodies that consume nicotine as soon as it enters thebloodstream, blocking it from reaching the brain and heart and negating thepleasure benefit of smoking.
"As far as we can see, the best way to treat chronicnicotine addiction from smoking is to have these Pacman-like antibodies onpatrol, clearing the blood as needed before nicotine can have any biologicaleffect," said Crystal, who was the lead investigator for the study.
The researchers fashioned their vaccine by taking thegenetic sequence of an engineered nicotine antibody—developed by co-author Dr.Jim D. Janda of the Scripps Research Institute—and placing it in anadeno-associated virus, informing the vaccine to make their way to hepatocytes(liver cells). Once the antibody reaches the hepatocytes, it inserts itsgenetic sequence into their nuclei, leading to the hepatocytes producing moreof the antibodies. Mice studies showed that the vaccine produced high levels ofthe antibody on a continuous basis, allowing little nicotine to reach thebrain.
"While we have only tested mice to date, we are veryhopeful that this kind of vaccine strategy can finally help the millions ofsmokers who have tried to stop, exhausting all the methods on the market today,but find their nicotine addiction to be strong enough to overcome these currentapproaches," said Crystal.
In addition to being a strong aid to smokers who have failedto quit with the aid of existing options, Crystal noted that given the safetyof the vaccine, there is potential to administer it during a person's youth,similar to the HPV vaccine. Such a tack is "only theoretically an option atthis point," however. Additionally, Crystal says the vaccine approach could beeffective in treating other kinds of addictions as well.
"We've already shown that we can do it for cocaine, with asimilar approach, so it's a platform strategy that could be used for any smallmolecule," he explains. "So we presume it would work for heroin,methamphetamines, oxycodone, those kinds of drugs. Whether you could develop itfor alcohol or not is more challenging because of the alcohol molecule. But formost of the addictive molecules, it should work."
The next step for the vaccine will be to test it in rats andthen primates as the researchers aim for eventual human testing. Safety is nota concern, Crystal notes, but it remains to be seen whether the process can beeffectively scaled up in humans to the point that sufficient amount ofantibodies are being produced to combat the average smoker's nicotine intake.
The study was funded by the National Institutes of Health,the National Foundation for Cancer Research and the Malcolm Hewitt WienerFoundation.
Additional co-authors include Dr. Martin J. Hicks, Dr.Jonathan B. Rosenberg, Dr. Bishnu P. De, Dr. Odelya Pagovich, Dr. Jian-pingQiu, Dr. Stephen M. Kaminsky, Dr. Neil R. Hackett and Dr. Stefan Worgall fromWeill Cornell Medical College, and Dr. Colin N. Young and Dr. Robin L. Davissonfrom Cornell University.

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