Gene therapy may hold the newest strategy to treat alcohol use disorder

Woman holding a glass of alcohol in her hands

Serious alcohol addiction, also called alcohol use disorder, has devastating impacts not only on those individuals and their families, but to the workforce, society and economy at large. And each year in the United States, 140,000 deaths are attributed to alcohol use disorder, according to the Centers for Disease Control and Prevention.

Today, FDA-approved therapies exist to help treat alcohol use disorder, but many people still suffer from relapse. And with staggering numbers of people estimated to have alcohol use disorder — 28.6 million American adults and nearly 900,000 adolescents, according to the National Survey on Drug Use and Health — the need for lasting treatments is great.

Researchers at The Ohio State University Wexner Medical Center and College of Medicine are exploring a new strategy that uses gene therapy to create a one-time, sustained treatment for patients with alcohol use disorder.

The study, published in the journal Nature Medicine, also involved researchers at the Oregon Health and Science University, the Oregon National Primate Research Center and the University of California San Francisco.

Understanding the role of alcohol use on the brain

Researchers have long studied how alcohol use affects dopamine in the brain. Dopamine is a neurostransmitter created by the brain that is commonly known as the “feel good” hormone. But chronic alcohol use alters nerve tracts in the brain involving the release of dopamine. These nerve tracts are part of the brain’s reward pathway, and when alcohol stimulates a “reward” response in the brain, this plays a major part in alcohol addiction.

Using gene therapy to target the brain’s response to alcohol

Ohio State’s gene therapy researchers are looking for ways to target the dopamine response to alcohol. In the study, which was conducted in primate models, researchers were able to show that sustained release of a hormone known as glial-derived neurotrophic factor (hGDNF) in a region of the brain called the ventral tegmental area (VTA) may prevent a return to excessive alcohol use after a period of abstinence. Furthermore, it may do so without disrupting other motivated behaviors.

“This gene-therapy approach targets changes in dopamine function in the brain’s reward pathway that are caused by chronic alcohol use,” says co-principal investigator and co-corresponding author Krystof Bankiewicz, MD, PhD, professor of Neurological Surgery in the Department of Surgery at The Ohio State University College of Medicine and director of the Brain Health and Performance Center at the Ohio State Wexner Medical center.

Read how gene therapy works

The role of abstinence and relapse in alcohol use disorder

People with alcohol use disorder commonly experience repeated cycles of abstinence followed by relapse, even when using one of the few FDA-approved drug therapies, Dr. Bankiewicz notes. But this gene therapy treatment shows promise to work as a one-time treatment without the need for other addiction rehabilitation services.

“Our findings suggest that this treatment can prevent relapse without requiring long-term treatment adherence by patients,” Dr. Bankiewicz says.

Read more about Dr. Bankiewicz’ work pioneering gene therapy treatments

As alcohol use disorder develops, alterations in the brain’s neural pathways become more pronounced.

They include reduced levels of dopamine release, reduced sensitivity of dopamine receptors and increased dopamine uptake. These changes lead to below-normal levels of dopamine in the pathway called a “hypodopaminergic” state in the brain. Researchers believe this state can compel excessive alcohol users to resume drinking even after periods of abstinence.

“At this time, there are no therapies that target circuits in the brain that are altered by sustained, heavy alcohol use,” says co-principal investigator and co-corresponding author Kathleen Grant, PhD, chief and professor of Behavioral Neuroscience at the Oregon National Primate Research Center.

“We believe this approach shows merit for further study as a promising therapy for AUD and possibly other substance-abuse disorders,” Dr. Bankiewicz adds.

This study was supported by grants from the National Institutes of Health (AA024757, AA013510, AA014091, AA010760, AA019431, OD011092, AA026117). Other researchers involved in this study were Victor S. Van Laar, Jerusha Naidoo, Piotr Hadaczek, Lluis Samaranch, The Ohio State University; Matthew M. Ford, Lauren E. Vanderhooft, Jodi L. McBride, Oregon National Primate Research Center, Oregon Health & Science University; Brianna George, Katherine M. Holleran, Emily G. Peck, Monica H. Dawes, Sara R. Jones, Wake Forest School of Medicine; Kousaku Ohno, John Bringas, John R. Forsayeth, University of California San Francisco.

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