Gene Therapy Might Offer a One-Time Treatment for Alcohol Addiction

Gene therapy might offer a one-time, sustained treatment for patients with serious alcohol addiction, also called alcohol use disorder, according to a new study led by a researcher at The Ohio State University Wexner Medical Center and College of Medicine.

The animal 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.

 

The study used an accepted primate model to show that sustained release of 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. 

People with alcohol use disorder (AUD) commonly experience repeated cycles of abstinence followed by relapse, even when using one of the few FDA-approved drug therapies, Bankiewicz notes.

 

Excessive alcohol use alters certain nerve tracts in the brain that involve the release of the neurotransmitter dopamine. These neurons make up the mesolimbic reward pathway, which plays a major role in alcohol and drug addiction.

 

These alterations become more pronounced as AUD develops. 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. 

 

Scientists think this “hypodopaminergic” state can compel excessive alcohol users to resume drinking 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. 

This study used an accepted rhesus macaque model of AUD to examine the practicality and effectiveness of delivering a viral vector into the brain to induce continuous expression of GDNF, diminish alcohol use and prevent post-abstinence resumption of drinking. 

 

Eight male rhesus macaques were involved; the vector was an adenoassociated virus vector that carried a gene for human glial-derived neurotrophic factor (AAV2-hGDNF). 

 

All eight animals were first habituated to the consumption of 4% alcohol. Then four animals were infused with the hGDNF vector directly into the VTA, located in the floor of the midbrain. Neurons in the VTA connect with the mesolimbic reward pathway. The remaining four animals served as controls. They were infused with sterile saline using the same surgical procedure.

Reference: Ford MM, George BE, Van Laar VS, et al. GDNF gene therapy for alcohol use disorder in male non-human primates. Nat Med. 2023. doi: 10.1038/s41591-023-02463-9