Treating Cocaine Addiction with Viruses
By Jason Socrates
Bardi
Scientists at The Scripps Research Institute have designed
a potentially valuable tool for treating cocaine addiction
by creating a modified "phage" virus that soaks up the drug
inside the brain.
They coated the virus with an antibody that binds to molecules
of cocaine and helps to clear the drug from the brain, which
could suppress the positive reinforcing aspects of the drug
by eliminating the cocaine high.
"Typically one would think of a virus as a bad entity,"
says principal investigator Kim D. Janda, who holds the Ely
R. Callaway, Jr. Chair in Chemistry and is an investigator
in The Skaggs Institute for Chemical Biology at Scripps Research.
"But we are taking advantage of a property it has—the
ability to get into the central nervous system."
The structure and design of the virus and its effect in
rodent models are described in an article that will be published
in an upcoming issue of the Proceedings of the National
Academy of Sciences.
Cocaine's Costs to Society
Americans spend more on cocaine, a chemical extracted from
the leaf of the Erythroxylaceae coca plant, than on
all other illegal drugs combined, says a White House Office
of National Drug Control Policy study that came out in the
mid-1990s. The study estimates that $38 billion was spent
on cocaine in the years 1988 to 1995 alone.
Cocaine's secondary costs to society due to cocaine treatment
and prevention programs, emergency room visits and other healthcare
costs, lost job productivity, lost earnings, cocaine-related
crime, and social welfare are estimated to be in the billions
of dollars annually—not to mention the drug's human toll.
According to the National Institute on Drug Abuse (NIDA),
about 1.7 million people regularly use cocaine in the United
States—a population larger than that of the city of Philadelphia—and
cocaine is the leading cause of heart attacks and strokes
for people under 35.
Once in the bloodstream, cocaine crosses the blood-brain
barrier and accumulates rapidly in the ventral tegmental area
of the brain. This area is connected by nerve cells to the
nucleus accumbens, the so-called pleasure center of the brain.
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 brain's pleasure
center, which produces a euphoric feeling in the user—a
quick rush that hits seconds after the user takes the drug
and lasts several minutes.
Relapse, unfortunately, is a reality for many addicts. Part
of the basis of relapse may be the strong positive reinforcement
of the high—doing the drug is so enjoyable for addicts
that they are conditioned to return to it.
Using Viruses in the Battle Against Cocaine
Several years ago, Janda and his colleagues designed an
antibody that was able to bind to cocaine. If the antibody
was present in the bloodstream, it would soak up the cocaine
like a sponge and prevent it from entering the central nervous
system where the drug exerts its narcotic effect. As a molecule,
cocaine is easily degraded by the body's natural chemistry,
and the sequestered cocaine would eventually disappear.
While this strategy was partially effective, the ability
of the antibody to curtail cocaine's effect proved to be limited
in animal studies. The antibody could not cross the blood-brain
barrier and cocaine could. In laboratory models, a large dose
of cocaine molecules could overwhelm the antibodies in the
blood, doing an end-run around them and leaking into the brain.
A few years ago, Janda and his graduate students Rocio Carrera
and Gunnar Kaufmann decided they wanted to target the cocaine
antibodies into the brain. That's when they set out to create
a new form of virus. This was done with collaborators Jenny
Mee and Michael Meijler in the Department of Chemistry and
Professor George Koob in the Department of Neuropharmacology
and the Pearson Center For Alcoholism and Addiction Research
at Scripps Research.
The researchers used filamentous phage—a type of virus
that infects bacteria—for the study. They inserted DNA
encoding an antibody that binds cocaine into the phage's genetic
code. When the modified phage were grown, they had hundreds
of these antibodies displayed on their surfaces.
Phage particles, like many types of viruses, have the ability
to enter the brain through the internasal passageway. Janda,
Carrera, and Kaufmann used this ability to deliver their antibody
into the central nervous system. The current study demonstrates
the ability of the antibody/phage to reduce one effect of
cocaine in rodent models (increased locomotion).
A similar technique could potentially be used for treating
the positively reinforcing aspects of the drug in humans,
say the scientists, but they cautioned that such an approach
has not been tested clinically and that even if proven safe
and effective it would be years before any such therapy were
available to patients.
The technique of displaying therapeutic proteins or peptides
on phage particles could be useful as a general way of delivering
therapies into the brain
The research article "Treating cocaine addiction with viruses"
is authored by M. Rocio A. Carrera, Gunnar F. Kaufmann, Jenny
M. Mee, Michael M. Meijler, Kim D. Janda, and George F. Koob
and is being published online the week of June 21 - 25, 2004
by the journal Proceedings of the National Academy of Sciences.
It will appear in a printed issue of PNAS later this year.
See http://www.pnas.org/cgi/doi/10.1073/pnas.0403795101
This research was supported by the National Institute on
Drug Abuse and The Skaggs Institute for Chemical Biology at
The Scripps Research Institute.
Send comments to: jasonb@scripps.edu
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