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Team creates novel vaccine that produces strong immunity against cocaine high

05.01.2011
The vaccine is poised to move quickly into human trials

Researchers from The Scripps Research Institute, Weill Cornell Medical College, and Cornell University have produced a long-lasting anti-cocaine immunity in mice by giving them a unique vaccine that combines bits of the common cold virus with a particle that mimics cocaine.

In their study, published January 4, 2011, in the advanced online edition of Molecular Therapy, the researchers say this novel strategy might be the first to offer cocaine addicts a fairly simple way to break and reverse their habit. The approach could also be useful in treating other addictions, such as to nicotine, heroin, and methamphetamine.

"Our very dramatic data shows that we can protect mice against the effects of cocaine, and we think this approach could be very promising in fighting addiction in humans," says the study's lead investigator, Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College.

"The vaccine suppresses the stimulant effects of the drug," said Scripps Research Professor Kim Janda, a co-author of the paper and a pioneer in the field of developing vaccines against addictive drugs such as cocaine. "Unlike other types of treatment, a vaccine such as this one does not interfere with the neurological targets of the drug, but instead blocks cocaine from ever reaching the brain in the first place."

In the new study, the vaccine effect lasted for at least 13 weeks, the longest time point evaluated in such an approach. Since the vaccine likely will not require multiple expensive infusions, the researchers hope that it can move quickly into human trials.

Clinically, this sort of therapy could be given to people in treatment programs to aid in their recovery. And, like most other types of treatment, it will only be useful for those who want the help.

"This vaccine would be most applicable for addicts who are who are interested in getting off the drug," said Janda, the Eli R. Callaway Jr. Chair in Chemistry and a member of the Skaggs Institute for Chemical Biology at Scripps Research. "In essence we view such vaccines as 'immuno-helpers' for treating substance abuse, and, in the case at hand, it might prove to be extremely useful for crack addicts whose relapse rate is exceedingly high."

The Drug

According to the latest statistics available from National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) in 2008 5.3 million Americans age 12 and older had abused cocaine in any form and 1.1 million had abused crack at least once in the year prior to being surveyed.

Cocaine, derived from the leaf of the Erythroxylaceae coca plant, is a highly potent drug that, as a salt, is either snorted or dissolved in water and injected directly into the bloodstream. The salt is also often neutralized to make an insoluble "free-base" form that is smoked.

Once ingested in the bloodstream, the drug crosses the blood–brain barrier and accumulates rapidly in the brain. "The brain levels rise very rapidly once cocaine is taken into the system," said Janda.

Moreover, the cocaine builds up in parts of the brain reward systems such as the nucleus accumbens. There, the cocaine molecules interfere with the normal regulation of dopamine by binding to dopamine transporters and blocking them from recycling the neurotransmitter.

This leads to the build-up of dopamine in the nucleus accumbens, which produces a euphoric feeling in the user—a quick rush that hits seconds after taking the drug and lasts several minutes. The psychological effect of this immediate reward is the basis for drug seeking in users. Compulsive users—addicts—will keep a perceived desire for the effect that will many times confound a recovering addict's best efforts to stay clean.

There is a common report among intravenous drug addicts that their first injection—that first snort of coke, shot of heroin, or puff of crack—produced the greatest feeling they had ever experienced. Many will also tell you that they too often spent their money, health, family, friends, and lives to try to get that feeling back.

"Unfortunately, there is no methadone for cocaine," said Janda. "Immunotherapy, however, might provide the added boost to keep a person from a major relapse, as after immunization a slip will not produce a drug effect."

Building on Previous Work

The Janda laboratory and the laboratory of George Koob, chair of the Committee on The Neurobiology of Addictive Disorders at Scripps Research, have , however, been working for more than a decade trying to find new approaches for combating addictive drugs of abuse such as cocaine.

In previous work, Janda and his synthetic team had developed several alternative formulations of anti-cocaine vaccines, which also acted by stimulating an active immune response against the drug in the bloodstream. However, a drawback of these prior vaccines as a lack of ready transferability to clinical trials.

In the new study, the team took advantage of a cocaine-hapten-scaffold (a cocaine-antigen that would elicit cocaine-producing antibodies) that Janda developed in the early 90s, this time chemically modifying it so that it could be attached to components of the adenovirus, a common cold virus. In this way, the human immune system was alerted to an infectious agent (the virus), but also learned to "see" the cocaine as an intruder. In this approach, the researchers used only the parts of the adenovirus that elicited an immune response, discarding those that produce sickness.

To test the effect of the vaccine, the researchers then injected billions of these viral concoctions into laboratory mice and found a strong immune response was generated against the vaccine. When put in test tubes, these antibodies gobbled up cocaine.

The scientists then tested the vaccine's effect on behavior and found mice that received the vaccine before cocaine were much less hyperactive while on the drug than unvaccinated mice. The effect was even seen in mice that received large, repetitive doses of cocaine. The cocaine doses reflected amounts humans might use.

While the path to a commercially available drug is a long one and the vaccine still needs to be tested extensively in humans, the researchers are hopeful their work will one day lead to a new way to battle cocaine addiction.

In addition to Crystal, Janda, and Koob, the study's authors included Martin J. Hicks, Bishnu P. De, Jonathan B. Rosenberg, Jesse T. Davidson, Neil R. Hackett, Stephen M. Kaminsky and Miklos Toth of Weill Cornell Medical College; Jason G. Mezey of Weill Cornell Medical College and Cornell University in Ithaca, New York; and Amira Y. Moreno and Sunmee Wee of Scripps Research. For more information, see http://www.nature.com/mt/journal/vaop/ncurrent/abs/mt2010280a.html .

The study was funded by the National Institute on Drug Abuse (NIDA) of the National Institutes of Health. The NIDA press office can be reached at 301-443-6245.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, Scripps Research currently employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

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