Alcohol use disorders (AUD) impose significant personal, social, and economic costs worldwide. Return to drinking is common among patients with AUD seeking treatment, resulting from cycles of repeated abstinence-relapse episodes, even with currently available pharmacotherapy.
Recently, researchers from Oregon Health and Science University published a research paper entitled "GDNF gene therapy for alcohol use disorder in male non-human primates" in the top international medical journal Nature Medicine. This study in non-human primates rhesus monkeys demonstrates that using adeno-associated virus serotype 2 (AAV2) to deliver human glial-derived neurotrophic factor (hGDNF) to the ventral tegmental area (VTA) of the midbrain can reduce alcohol use and prevent alcohol addiction from relapsing after abstinence.
Figure 1. AAV2-hGDNF delivery to the VTA. (Ford M M, et al., 2023)
Professor Krystof Bankiewicz, the corresponding author of the paper, said that the gene therapy targets changes in dopamine function in the mesolimbic reward pathway caused by chronic alcohol consumption. Experimental results show that this gene therapy can prevent alcohol relapse after abstinence, potentially providing a one-time, continuous treatment for patients with severe alcohol addiction, also known as alcohol use disorder.
GDNF is a growth factor, meaning it stimulates a rapid increase in cell numbers, which increases the function of neurons in the brain that synthesize dopamine, a feel-good chemical released in the brain. Long-term alcohol consumption effectively reduces the release of dopamine. Studies have shown that people diagnosed with severe AUD, as well as rodent and non-human primate models of AUD, have impaired dopamine release mechanisms in certain areas of the brain, which together result in a "hypodopaminergic state." Repeated ethanol use induces neuroadaptations in dopaminergic signaling in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of the reward circuit is associated with reinstatement of drinking behavior.
In this study, the research team conducted studies in rhesus monkeys, a non-human primate, using AAV2 to deliver human GDNF. AAV2-hGDNF was injected into the VTA of the midbrain of 8 rhesus monkeys to express glial-derived neurotrophic factor, and the other 4 rhesus monkeys were injected with sterile saline according to the same procedure as the control group.
These rhesus monkeys were conditioned to drink 4% alcohol before treatment. After treatment, the monkeys in the treatment group continued to express hGDNF in their brains and eliminated the relapse of drinking behavior during the subsequent 12 months of repeated abstinence-reintroduction challenges. This behavioral change is accompanied by neurophysiological modulation of nucleus accumbens dopamine signaling that counteracts the hypodopaminergic signaling state associated with chronic alcohol use. This suggests that GDNF gene therapy targeting the VTA of the midbrain can reduce alcohol use and prevent relapse after abstinence, and may be a potential therapeutic strategy for alcohol use disorder (AUD).
The use of gene therapy to treat central nervous system disorders is a mature and rapidly expanding field, and MR-guided delivery of AAV2 vectors into the VTA has been found to be safe and tolerable in other nonhuman primates. The safety of intraparenchymal AAV2-hGDNF delivery and expression has also been demonstrated in NHPs, and putaminal delivery of AAV2-hGDNF is currently being evaluated in clinical trials as a treatment for PD, while further work is needed to assess dosing for targeted therapies.
Reference
Ford M M, et al. GDNF gene therapy for alcohol use disorder in male non-human primates. Nature Medicine, 2023: 1-11.