Debunking myths on genetics and DNA

Monday, July 9, 2012

A nicotine vaccine could be the key to quit smoking

It's been a while since I last talked about gene therapy, and this recent study gave me the perfect chance to reopen the topic: a research group tested a vaccine against nicotine addiction in mice. But wait... how can a vaccine work against... a molecule?

Once inhaled, nicotine reaches the brain within 10-20 seconds. Here, it activates one of the dopaminergic pathways in the brain, which involves the transmission of dopamine from one region of the brain to another. Dopamine is a neurotransmitter, in other words, it is used by nerve cells to communicate with each other. Numerous studies have found the level of dopamine transmission in the brain to be directly correlated with rewards. Nicotine, as well as other drugs like cocaine and meth, become highly addictive by acting on the dopamine transmission pathways. When in withdrawal, the production of dopamine is down-regulated and compensated withe the up-regulation of other transmitters.

Vaccination as a possible way to cure drug addictions has been studied for nearly 40 years for number of drugs, not just nicotine.
"Vaccines consisting of the drug linked to a foreign carrier protein elicit the production of drug-specific antibodies that bind drug in serum and extracellular fluid, reduce the unbound drug concentration, and reduce drug distribution to brain. Immunization has been shown to block or attenuate a variety of drug-induced behaviors in rats that are relevant to addiction, including locomotor activation, drug discrimination, and drug self-administration [1]."
The anti-drug antibodies bind to the drug molecule, effectively sequestrating it while still in blood circulation and thus preventing it to reach the brain. Less drug in the brain means less dopamine-induced reward effect, which causes the addiction. Therefore, the hope is to reduce drugs' addictive powers by preventing it to reach the brain.

In [2], Shen et al. et al. review a number of clinical trials that tested nicotine vaccines, but conclude that
"Overall, these trials have not demonstrated nicotine vaccines to be superior to placebo when including all vaccinated subjects, because only a third of those vaccinated subjects developed sufficient levels of antibody to block the effects of nicotine."
In fact, so far clinical trials have yielded inconsistent results, and often require boosts to keep the antibody concentrations high.

Is that the end of a nicotine vaccine? Certainly not. While research continues for a vaccine in the classical sense, in a recent study published in Science Translational Medicine [3], Hicks et al. explored a new way: since the body can't make the antibodies on its own, they used gene therapy in mice to provide the genes that produce anti-nicotine antibodies.
"We hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector expressing high levels of an anti-nicotine antibody would persistently prevent nicotine from reaching its receptors in the brain."
If you need a refresher on adeno-associated viral vectors, check-out this earlier post. Mice that received the single administration were followed for 18 weeks, during which high concentrations of nicotine binding antibodies were observed. In treated mice the concentration of nicotine in the brain was 15% lower than untreated mice. Drug sequestration in the blood stream was seven times greater in treated mice than untreated mice.

It remains to be seen whether these results will be matched in humans. If effective, one could envision school vaccination programs to prevent teenagers from starting to smoke. However, one big caveat that concerns both the classic vaccine and the gene therapy route is whether the "drug sequestration" induced by the antibodies could force people to smoke considerably more in order to achieve the same effects they experienced before they were vaccinated. This would be devastating as people would end up taking higher doses of carcinogens in their bodies. Furthermore, as with all gene therapy treatments, comes the usual warning that these therapies induce permanent changes in the body whose effects often are not detectable until much later in life.

[1] D. E. Keyler,, S. A. Roiko,, E. Benlhabib,, M. G. LeSage,, J. V. St. Peter,, S. Stewart,, S. Fuller,, C. T. Le and, & P. R. Pentel (2005). MONOCLONAL NICOTINE-SPECIFIC ANTIBODIES REDUCE NICOTINE DISTRIBUTION TO BRAIN IN RATS: DOSE- AND AFFINITY-RESPONSE RELATIONSHIPS DMD vol. 33 no. 7 1056-1061 DOI: 10.1124/dmd.105.004234

[2] X Y Shen1, F M Orson1,2 and T R Kosten (2012). Vaccines Against Drug Abuse Clinical Pharmacology 6(1), 277-70. DOI: 10.1038/clpt.2011.281 DOI: 10.1038/clpt.2011.281

[3] Martin J. Hicks1,, Jonathan B. Rosenberg,, Bishnu P. De1,, Odelya E. Pagovich,, Colin N. Young,, Jian-ping Qiu,, Stephen M. Kaminsky,, Neil R. Hackett,, Stefan Worgall1,, Kim D. Janda,, Robin L. Davisson and, & Ronald G. Crystal1 (2012). AAV-Directed Persistent Expression of a Gene Encoding Anti-Nicotine Antibody for Smoking Cessation Sci Transl Med 27 June 2012: Vol. 4, Issue 140, p. 140ra87 DOI: 10.1126/scitranslmed.3003611


  1. antisocialbutterflieJuly 9, 2012 at 8:13 PM

    This is pretty awesome. I hadn't realized that you could fit a whole antibody in AAV. I have mixed feelings about the topic however. Whenever I see studies like this I feel compelled to note that there is a difference between nicotine and smoking. It's one of those "all squares are rectangles but not all rectangles are squares" issues. Nicotine itself is actually a fairly good cognitive enhancer and alone really isn't much worse than caffeine. It's the method of administration that is at issue. I'm not saying that this won't be a good thing or help a lot of people. The distinction is just a pet peeve.

    1. Not a pet peeve at all, I think you're absolutely right!

      Question: my understanding was that they fit the gene that encodes the antibody in the AAV... is that what you mean or did I misunderstand?

    2. antisocialbutterflieJuly 9, 2012 at 8:47 PM

      Sorry. I'm recouping from a 24 hour data collection.

      Yes I didn't know that you could fit an antibody gene into an AAV. I would have thought that you could squeeze an F(ab) but not a full heavy and light chain. Though a quick google search and some minor math indicate that the coding region of a heavy and light chain should add up to just under 2 kb which puts it well within packable size. I'm just being dense today.

    3. No you're not, I just wanted to make sure I understood right.

      Sorry, I know how frustrating data can be... :-(

      Good night, and thanks for your comments!


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