Top Investigators Awarded for Novel Approaches to Addiction Research

Fran Lowry

September 28, 2010

September 27, 2010 — Four of the nation's top scientists who specialize in the treatment of drug addiction have become the first recipients of the National Institute on Drug Abuse (NIDA) Avant-Garde Awards for Medications Development Research.

Each will receive $500,000 per year for 5 years to support their research projects, which will explore immunotherapy, gene therapy, a compound originally isolated from a Chinese herb, and an enzyme inhibitor, to treat cocaine and tobacco addiction.

Dr. Ivan Montoya

"NIDA has had an Avant-Garde award for HIV/AIDS research," Ivan Montoya, MD, MPH, deputy director of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, told Medscape Medical News. "This is the first time that we have one for innovative medications, and we are very excited about the innovation and the uniqueness of this new research."

Andrew Norman, PhD, a professor in the Psychiatry and Behavioural Neuroscience Department of the University of Cincinnati in Ohio, is hoping to develop a human monoclonal antibody against cocaine that will be suitable for immunotherapy against addiction relapse.

When injected into the bloodstream, the antibody, designated h2E2, will attach to cocaine, preventing it from entering the brain and thereby limiting its behavioral effects.

Dr. Andrew Norman

Dr. Norman and his colleague W. James Ball, PhD, professor of pharmacology and cell biophysics at University of Cincinnati, have already demonstrated that a similar mouse-human antibody, 2E2, reduces cocaine's effects in a rat model of relapse.

Won't Get No Kick From Cocaine

"All of cocaine's effects related to its addictive properties occur in the brain. If we can stop it from getting into the brain, we should be able to prevent all of cocaine's effects relative to its abuse potential," Dr. Norman explained to Medscape Medical News.

The trick is to develop a human antibody that will be efficacious and safe for use in humans, Dr. Norman continued. "Dr. Ball had made a human monoclonal antibody against digoxin, and when I asked if he could do that with cocaine, he said ‘yes, that looks doable — tricky but doable'. So we formed a collaboration, and the rest, as they say, is history."

Dr. Ball had made a human monoclonal antibody against digoxin, and when I asked if he could do that with cocaine, he said ‘yes, that looks doable — tricky but doable'. So we formed a collaboration, and the rest, as they say, is history.

They are hoping that they will be able to figure out a way to produce the human monoclonal antibody in a way that is commercially viable.

"It turns out that the antibody is not produced very well and not at the level we need. This grant will help us discover how to overcome this," Dr. Norman said.

The path to successful humanizing of animal antibodies is often fraught with glitches, both the researchers admit, but they refuse to give up. As Dr. Norman says, "Dogged persistence has been one of the key things that has kept us going. I wasn't the most patient person before, but I'm learning."

Dr. W. Stephen Brimijoin

W. Stephen Brimijoin, PhD, professor of pharmacology at the Mayo Clinic, Rochester, Minnesota, is also working on ways to thwart cocaine addiction relapse. In this case, it is through gene therapy.

The idea is based on a lot of animal data that he and his team have accumulated during the past few years, showing that it is possible to block the entry of cocaine into the brain with cocaine destroying enzymes that have been engineered from a natural human enzyme that is extremely benign and without any physiologic effects.

"Our goal is to create a long-lasting barrier that will prevent cocaine from reaching the reward centers in the brain and driving addiction behaviors," he explained in an interview.

Medical Treatment for Motivated Users

Statistics show that almost 90% of people who are trying to kick their cocaine habits and who have become abstinent relapse within a year of their rehabilitation treatment. Gene therapy can help these people, Dr. Brimijoin said.

Our goal is to create a long-lasting barrier that will prevent cocaine from reaching the reward centers in the brain and driving addiction behaviors.

"We don't see this as a mass treatment for problem users but as a medical treatment for motivated users who want to get clean and stay that way and who know how dangerous and hard and risky that is. So if this therapy is going to work at all, you have to be able to deliver it and sustain its level for quite a while.

"The danger of relapse remains high for months — up to 2 years. There's a reasonable probability that if you could sustain abstinence for a couple of years, you would be well on the road to recovery. So that's our goal."

Dr. Brimijoin says he has been interested in these enzymes for decades.

"I'm an old guy who has got a young whippersnapper award here. I've been working for years and years and years on a family of enzymes that fascinated me because they were in neurons and they seemed to be involved in many critical physiological and behavioural systems.

"A little over 10 years ago, it slowly dawned on me that 1 very interesting ability of this family of enzymes was that they played a role in the metabolism of psychoactive drugs, in particular, cocaine."

Dr. Brimijoin's grant will allow him to demonstrate that the enzyme works "in the most rigorous and thorough way" and identify whether any toxic effects are associated with it and then to present the U.S. Food and Drug Administration with high-quality data in support of an investigational new drug (IND) to pave the way for a clinical trial.

He added that he knows that the NIDA has high expectations for his research.

"I told my lab when we got this grant that an RO1 award is sort of the basic currency of academic research. It is like a research hunting license; you go out there, snoop around, find some interesting stuff. Great. This one is more like a large prepaid order for moose meat, and you'd better be prepared to deliver. We're gonna do our darndest."

Dr. Jia Bei Wang

Chinese Herbal May Be Another Contender

Another warrior in the fight against cocaine addiction is Jia Bei Wang, MD, PhD, professor of pharmacology at the University of Maryland, Baltimore.

Dr. Wang describes her research project as "straightforward."

"We found a drug that has been used in China for 40 years as a pain killer and a tranquilizer that may be effective for the treatment of cocaine addiction," she explained.

We found a drug that has been used in China for 40 years as a pain killer and a tranquilizer that may be effective for the treatment of cocaine addiction.

The drug is I-THP, a major active compound isolated from the Chinese herb yanhuso (Corydalis yanhuso), which is marketed as Rotundine in China.

Dr. Wang has had a long-standing interest in finding the mechanisms of drug addiction. And, being from China herself, she also knows a lot about Chinese herbal medicine.

She became interested in studying I-THP after a literature search uncovered studies, mostly by Chinese scientists, that showed that I-THP acts on dopamine receptors and that it significantly attenuates cocaine self-administration and brain-stimulation reward in rats.

The compound has also been shown to reduce craving and also to increase abstinence rates among heroin addicts after detoxification.

"The NIDA award is a great opportunity for me to move this research project forward. If you want to get a drug, especially one that has never been used in the United States, to be approved for the treatment of one of the most serious illnesses in the country where there is no medication available, then you have to go through this rigorous regulatory procedure to get your IND," said Dr. Wang.

"After we get our IND we will test this in humans in a phase 1 trial, and then later we will test it in cocaine addicts to see whether it will be effective in a phase 2 trial."

Helping Smokers "Kick Butt"

Dr. Daniele Piomelli

Taking up the research challenge on another front, this time tobacco addiction, is Daniele Piomelli, PhD, professor of pharmacology and Louise Turner Arnold Chair in Neurosciences at the University of California, Irivne.

Dr. Piomelli and his team are hoping to develop a drug that targets the cannabinoid system to help people who are addicted to cigarettes kick the habit.

"Available treatments for smoking cessation are neither very effective nor very safe. Many people who want to stop smoking do not respond well to them or suffer from side effects that lead to treatment discontinuation," Dr. Piomelli, who is also director of drug discovery and development at the Italian Institute of Technology in Genoa, Italy, told Medscape Medical News.

Our compounds work through a different mechanism than those used by available drugs...We hope they will be proven to be both safe and effective for the significant proportion of patients who are not well served by current medications.

"Our compounds work through a different mechanism than those used by available drugs and have been shown to be safe in initial clinical studies. We hope, therefore, that they will be proven to be both safe and effective for a significant proportion of patients who are not well served by current medications," he said.

The compounds inhibit an enzyme called fatty acid amide hydrolase (FAAH). This enzyme degrades the brain neurotransmitter anandamide, which regulates many important functions, including pain, mood, and the response to rewarding stimuli.

Dr. Piomelli and his researchers have discovered that the FAAH inhibitor they have developed, FAAH inhibitor URB597, blocks ongoing nicotine use and prevents relapse into nicotine use in monkeys.

"The mechanism by which URB597 produces this effect is not fully clear yet, but likely involves boosting anandamide's actions in the brain. This may turn off nicotine's ability to hijack brain rewarding systems, such as the dopamine system, which are responsible for nicotine's powerful addictive properties," he explained.

Dr. Montoya said the NIDA is very excited about these research projects and hopes they bear fruit. A particular hope is that they will spark the pharmaceutical industry's interest in pursuing more studies in this area.

"It is very sad to see that we have a major public health problem not only with cocaine addition but with marijuana addiction and opioid and nicotine dependence. The pharmaceutical industry does not see those diseases as priorities, perhaps because they are difficult to treat, perhaps because they don't see a drug to treat addiction as a money maker," he said.

But the reality is that agents to fight drug addiction have a huge potential to make money for their manufacturers. The NIDA has begun partnering with more and more companies "to get them excited about our research and entice them to believe there is opportunity in drug abuse pharmacotherapy," Dr. Montoya said.

"We are hoping that the Avant-Garde awards will allow the investigators to develop new compounds and that this will provide new opportunities for industry to go on and develop these compounds further."

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