Recovery Act grantee leads integrated research center studying the pharmacogenomics of addiction
By Susan Johnson
September 6, 2011
Recovery Act Investment: “Mayo Clinic Program for Individualized Treatment of Alcohol Dependence,” David A. Mrazek, Mayo Clinic; 2009: $1,231,613 (1P20AA017830-01); 2010: $1,268,395 (5P20AA017830-02). Funded by the National Institute on Alcohol Abuse and Alcoholism.
Publications listing this Recovery Act Investment as providing grant support: Lee MR, et al. Acamprosate reduces ethanol drinking behaviors and alters the metabolite profile in mice lacking ENT1. Neuroscience Letters, 2011;490:90–95.
Kim, J-H, et al. Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One, 2011;6(1):e16331.
The Problem:
According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), nearly 8,000,000 Americans are addicted to alcohol1. Of the fraction who get help, only some find any given treatment to be effective. For example, the drug acamprosate reduces alcohol cravings in some people—but not others—by maintaining the brain’s chemical balance during withdrawal. Why doesn’t acamprosate help everyone? How can doctors predict which patients will benefit from it?
The Mayo Clinic in Rochester, Minnesota is developing a research program to answer these types of questions and to use the answers to help patients. Beginning with privately donated funds, Mayo brought in a new scientific team to study the genetics of addiction hoping to develop this nascent team into an integrated program where lab and clinical scientists would work together to translate discoveries into better alcoholism treatments. To launch this program, the investigators, led by Dr. David Mrazek, applied for an exploratory research center grant from NIAAA to create what they called the “Mayo Clinic Program for Individualized Treatment of Alcohol Dependence.” Their plan was to begin by studying the genetic and neurochemical bases of acamprosate treatment response using both mice and human subjects.
“What we’re doing that is especially unique is taking this integrative research model and directing it to pharmacogenomics, seeing how genetics affects alcoholism treatment. This is a narrow but an important focus.” -Mrazek
Unfortunately, their grant application barely missed NIAAA’s tight cutoff for these highly competitive research funds. Without this grant, the team’s potentially transformative research program would have developed much more slowly, said Mrazek, or even been shut down, if the investigators could not find alternative funding sources.
“If we wanted to continue work, we needed to find alternative support. It was critical that we have this [exploratory] grant, or the entire operation would have slowed down and ultimately closed…What we needed most of all was an infrastructure grant to hold us together.” -Mrazek
Help From the American Recovery and Reinvestment Act (ARRA):
In a stroke of luck for the Mayo investigators, however, a perfectly timed infusion of funds from ARRA allowed NIAAA to expand the number of applications the Institute was able to support. But there was a hitch: Although the collaborators had planned on a four-year grant, ARRA required them to finish their project in two years.
“It pushed us to get moving. We couldn’t really jog, we had to start running right from the very beginning. We got twice as much done in the first two years and that was fantastic.” -Mrazek
This meant that the investigators had to kick into high gear and alter their original plans. They hired teams of clinicians, patient coordinators, and data managers to search for study participants in three additional towns in order to complete enrollment more quickly. As a side benefit, this resulted in a more ethnically and socioeconomically diverse set of patients than would have participated otherwise, explained Mrazek; in addition, many of the patients were not being treated for their alcoholism before joining the Mayo research.
David A. Mrazek, M.D., chair of the Department of Psychiatry and Psychology and program director of the Mayo Clinic Program for Individualized Treatment of Alcohol Dependence at the Mayo Clinic
The ARRA funding also supported the mouse work of the preclinical core, led by Dr. Doo-Sup Choi. As a result of this support, these investigators recently released two reports on the effects of a particular alcoholism-linked gene on alcoholics’ response to acamprosate.
Answers Emerge
The gene makes a protein called ENT1 that controls the flow of a brain signaling chemical in and out of cells in response to alcohol. Mice without ENT1 get less “drunk” and tend to drink more than the normal mice with the ENT1 protein. While humans all possess ENT1, some people have a different version of the protein. In research published in early 2011 in the journals Neuroscience Letters and PLoS One, Choi’s group found that one variant of human ENT1 has a similar biochemical effect in the cell as in the mice lacking ENT1, suggesting that these mice may be a good model for studying people with this variant of ENT1. They also found that these people—similar to the mouse model—were more likely than others to become alcoholics in the first place.
“This is pretty exciting science—but it’s a slow process. We can carve out one brain system at a time and try to make some progress.” -Mrazek
Doo-Sup Choi, Ph.D., Associate Professor of Psychiatry and Associate Professor of Pharmacology, Mayo Clinic
The researchers found that acamprosate treatment reduced alcohol consumption by the heavy-drinking mice without ENT1, but it didn’t seem to have any effect on the normal mice’s drinking habits. The investigators used magnetic resonance imaging to peer into an important brain area for addiction called the nucleus accumbens—which can’t be imaged in humans—and saw that acamprosate had a different effect on the brain’s addiction-related chemical pathways in the mice lacking ENT1 compared to the other mice. The researchers also found that both mice without ENT1 and people with the specific variant of ENT1 are more prone to the dangerous seizures that can accompany alcohol withdrawal in lifelong heavy drinkers—“the end stage of a horrible disease,” said Mrazek.
Looking to the Future
The researchers will continue bringing the findings from their mouse research into the clinic, hoping to develop genetic tests that can determine which patients may benefit from treatment with particular medications, such as acamprosate. The ARRA-funded interdisciplinary group also is exploring the relationship between variation across the human genome and response to acamprosate and imaging the brain biochemistry of patients on acamprosate treatment. They will soon publish more details of their work in mapping the biochemical networks of alcohol addiction in the brain.
This center allows us basic scientists and the clinicians to talk; it has a synergistic effect. Although it’s only been two years, we’ve established a wonderful infrastructure and we think we are ready to move on to the next level.” —Choi
Mrazek hopes to receive support to build a training program for new scientists who are interested in Mayo’s collaborative research model for alcoholism treatment. By training new scientists, the research program’s important work will move forward into the future.
Mrazek is optimistic that the Mayo Clinic Program for Individualized Treatment of Alcohol Dependence as a whole will secure longer-term funding after its ARRA support is complete. Meanwhile, the program’s clinical and preclinical investigators meet every Monday at noon to keep each other in the loop on their research and to find new ways to create productive synergy between their different areas of expertise. Their vision is to harness the energy they’ve created to find new ways to help people escape the disease of addiction.
1 Twelve-month prevalence and population estimates of DSM-IV alcohol dependence by age, sex, and race-ethnicity: United States, 2001–2002 (NESARC)
http://www.niaaa.nih.gov/Resources/DatabaseResources/QuickFacts/AlcoholDependence/Pages/abusdep2.aspx
