The results of a study in nonhuman primates suggest that a form of gene therapy currently being evaluated to treat Parkinson’s disease (PD) may dramatically reduce alcohol use by resetting the brain’s dopamine reward pathway in animals predisposed to heavy drinking.
The study, headed by researchers at Oregon Health & Science University (OHSU), showed that implanting a viral vector carrying the gene for human glial-derived neurotrophic factor (GDNF) directly into a specific area of the brains of heavy-drinking rhesus macaque monkeys led to a dramatic drop in their alcohol consumption. The team said that while the gene therapy procedure does involve brain surgery, it may be useful in the most severe cases of alcohol use disorder (AUD).
“This was incredibly effective,” said Kathleen Grant, PhD, professor and chief of the division of neuroscience at OHSU’s Oregon Primate National Research Center, or ONPRC. “Drinking went down to almost zero. For months on end, these animals would choose to drink water and just avoid drinking alcohol altogether. They decreased their drinking to the point that it was so low we didn’t record a blood-alcohol level.” Grant is co-senior author of the team’s published paper in Nature Medicine, which is titled, “GDNF gene therapy for alcohol use disorder in male non-human primates.” In their paper, the team concluded, “These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD … Given the profound efficacy of GDNF gene therapy to mitigate reintroduction-associated alcohol intake in our NHP model, we believe that this therapeutic approach could be a promising therapy for AUD, and possibly have efficacy to other substance use disorders.”
AUD causes enormous personal, social, and economic costs globally, the authors wrote, with AUD and alcohol-related deaths causing an estimated worldwide death toll of 2.4 million. “Recent epidemiological studies on alcohol consumption estimate an annual cost of $249 billion on the U.S. economy associated with alcohol use, with 140,000 deaths per year in the United States attributed to alcohol use disorder (AUD) …” they continued.
There are also few FDA-approved pharmacotherapies available, and adherence to continued medication is one of the most significant obstacles to treatment success, the team continued. “Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies … Therapeutic approaches that directly target the underlying brain circuitry adaptations concurrent with sustained heavy drinking are missing and would add a new dimension to available treatments for patients with AUD.”
GDNF is a growth factor—meaning it stimulates cells to rapidly increase in number—which enhances the function of neurons in the brain that synthesize dopamine, a feel-good chemical released in the brain. And chronic drinking effectively decreases the release of dopamine. Studies have shown that people diagnosed with severe AUD, as well as rodents and nonhuman primate models of AUD exhibit impaired dopamine release mechanisms within certain areas of the brain, which together result in a “hypodopanergic state,” the team continued. “Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior.”
Grant further noted, “Dopamine is involved in reinforcement of behavior, and in people finding certain things pleasurable. Acute alcohol use can increase dopamine. However, by drinking it chronically, the brain adapts in such a way that it decreases the release of dopamine. So when people are addicted to alcohol, they don’t really feel more pleasure in drinking. It seems that they’re drinking more because they feel a need to maintain an intoxicated state.”
For their study, the team looked to enhance dopamine by using an AAV2 viral vector to deliver human GDNF (hGDNF) to the ventral tegmental area (VTA) of the brains of a group of four rhesus macaque monkeys that voluntarily and heavily drink ethanol diluted in water. Another four animals received sham treatment. “We examined the utility and efficacy of delivering AAV2 vector into the VTA to induce constitutive expression of GDNF, ablate alcohol use, and prevent post-abstinence resumption of drinking using a rhesus macaque model of AUD,” the investigators wrote. “We posited that the sustained GDNF expression in the VTA will selectively prevent excessive drinking following abstinence while not disrupting other motivated behaviors.”
Veterinarians at the ONPRC used magnetic resonance imaging to guide insertion of the AAV2-GDNF construct into the ventral tegmental area of the rhesus monkey brain. The adeno-associated virus is a single-stranded DNA virus that does not cause disease in its subject. The procedure is already used in adult patients with Parkinson’s disease and in children to treat a rare genetic disorder known as aromatic L-amino acid decarboxylase deficiency that, among other symptoms, causes difficulty with movement.
The results were dramatic. After the rhesus macaque monkeys underwent the procedure, researchers found that alcohol consumption in those receiving the AAV2-GDNF construct dropped by more than 90% compared with a control group, and the treatment prevented post-abstinence resumption of drinking. “GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence–alcohol reintroduction challenges,” the authors stated. “This durable effect is key to overcoming the cycles of increased drinking following attempts at decreasing alcohol intake that current pharmacological therapies are prone to, while providing lasting change to the underlying DA signaling system dysfunction associated with AUD.”
Grant added, “The monkeys that were treated with this gene permanently started overexpressing dopamine and they decreased their drinking substantially.” The treatment does permanently alter the brain through surgery, so would be limited to those with the most severe forms of alcohol use disorder, Grant pointed out. “It would be most appropriate for people who have already shown that all our normal therapeutic approaches do not work for them,” she said. “They are likely to create severe harm or kill themselves or others due to their drinking.”
Nevertheless, the authors wrote, “The use of gene therapy for treating CNS disorders is an established and rapidly expanding field,” and the MR-guided delivery of AAV2 vector into the VTA has been found to be safe and tolerable in other nonhuman primates, and has been safely carried out in the midbrain of human patients, the team noted. “The safety of intraparenchymal AAV2-hGDNF delivery and expression has also been demonstrated in NHP, and putaminal delivery of AAV2-hGDNF is currently being evaluated as a treatment for PD in clinical trials.” Acknowledging that further work is needed to evaluate dosing for targeted treatment, the authors concluded “… these data demonstrate the promise of a one-time AAV2-hGDNF infusion after chronic daily alcohol drinking has been established to address the underlying neurophysiopathology and provide a much-needed treatment for patients with AUD.”
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