Resetting the Brain’s Reward Pathway: Gene Therapy’s Breakthrough in Alcohol Addiction
Recent research from The Ohio State University Wexner Medical Center and College of Medicine has highlighted the potential of gene therapy as a once-off, sustainable treatment for alcohol use disorder (AUD). Collaborative efforts with the Oregon Health and Science University, the Oregon National Primate Research Center, and the University of California San Francisco led to this groundbreaking animal study, which was published in Nature Medicine.
Utilizing an acknowledged primate model, the study unveiled that the continuous release of glial-derived neurotrophic factor (hGDNF) in the ventral tegmental area (VTA) of the brain could deter a relapse into excessive alcohol consumption following an abstinence period. Intriguingly, this does not interfere with other motivation-driven behaviors.
According to Dr. Krystof Bankiewicz, one of the main researchers, the approach focuses on rectifying changes in dopamine function within the brain’s mesolimbic reward pathway, alterations caused by chronic alcohol consumption. This potential solution might keep relapses at bay without demanding ongoing patient compliance, addressing the notorious challenge of repeated relapse cycles even when patients are on FDA-approved medications.
Understanding the Problem: Alcohol Use Disorder (AUD)
Chronic alcohol consumption modifies nerve tracts linked with dopamine release in the brain. This impacts the mesolimbic reward pathway, central to alcohol and drug addiction. As AUD advances, the changes intensify, leading to decreased dopamine release, diminished dopamine receptor sensitivity, and increased dopamine uptake, eventually causing dopamine scarcity. This “hypodopaminergic” state might be the driving force behind the craving to drink after sobriety.
Dr. Kathleen Grant of the Oregon National Primate Research Center emphasizes the absence of therapies addressing the brain circuits modified by extensive alcohol intake.
Researchers used a rhesus macaque model, recognized for AUD research, to probe the viability and effectiveness of using a viral vector for inducing the consistent expression of GDNF, consequently curbing alcohol consumption and thwarting drinking relapses post-abstinence.
In the study, eight male rhesus macaques first got accustomed to 4% alcohol. Half were then infused with a viral vector, AAV2-hGDNF, directly into the VTA. The other half, serving as controls, were infused with sterile saline.
AAV2-hGDNF infusion considerably curtailed alcohol consumption over multiple cycles of abstinence and alcohol reintroduction.
GDNF-treated subjects had undetectable blood ethanol levels for the majority of the study.
Controls displayed sustained high alcohol and blood ethanol levels.
Dr. Bankiewicz believes this gene therapy holds promise for AUD and potentially other substance-abuse disorders based on their primate model results.
The Scope of AUD
According to the 2021 National Survey on Drug Use and Health:
11.3% of American adults (28.6 million) and 3.4% of adolescents (894,000) suffered from AUD.
12% of alcohol consumers qualify for AUD according to the Diagnostic and Statistical Manual for Mental Disorders 5th edition.
Alcohol use disorder is attributed to 140,000 U.S. deaths annually, as per the CDC.
In essence, this research underscores the transformative potential of gene therapy in treating AUD, which is an increasingly concerning health issue. Further study is eagerly anticipated.