Gene Therapy Reduces Alcohol Consumption in Monkeys by 90% In Just One Year

This specific gene therapy method entails the introduction of a genetically altered virus (depicted in the image above) into the brain. The aim is to trigger an increase in dopamine synthesis, addressing its deficiency observed in individuals with alcohol use disorder.

A single-dose gene therapy, initially developed to treat Parkinson’s disease and tested on monkeys, has shown remarkable effects in treating alcohol consumption disorder. By resetting the dopaminergic cycle, the treatment reduced alcohol consumption by half within a few weeks and by 90% after one year. However, the therapy has limitations and could only be considered (if validated) as a last resort, particularly for the most severe cases.

A gene therapy originally developed for Parkinson’s disease, which was tested on monkeys, has shown remarkable effects on alcohol consumption disorder induced by an increase in dopamine secretion, thereby stimulating the brain’s reward system. Nevertheless, chronic and excessive alcohol consumption gradually impairs this system by reducing hormone release and the sensitivity of dedicated neuroreceptors. Those with alcohol-related disorders develop a form of drug tolerance, where dopamine secretion decreases over time, driving them to consume more to achieve intoxication.

Scientists attribute relapses despite withdrawal efforts to hypodopaminergia. Even with advanced therapies, many individuals undergoing alcohol withdrawal experience cycles of abstinence and relapse. “We know that we can get people with alcohol use disorder to stop drinking for short periods of time,” says Kathleen Grant, a neuroscientist at Oregon Health & Science University (OHSU) and co-author of the new study. “But the desire to drink again often supersedes taking their medications,” she explains.

Globally, an estimated 237 million men and 46 million women suffer from alcohol use disorders. Currently, no available therapy targets the altered neural circuits responsible for these disorders. The newly proposed gene therapy by OHSU specifically focuses on these circuits. Initial in vivo results, available on the Nature Medicine platform, are remarkable, showing high and potentially long-term effectiveness.

The treatment involves a gene encoding glial cell-derived neurotrophic factor (GDNF). This protocol has been used previously to treat Parkinson’s disease and a rare genetic disorder causing aromatic L-amino acid decarboxylase deficiency, both characterized by movement difficulties due to reduced dopamine secretion. The therapy is delivered via a single-stranded adenoviral vector directly to the ventral tegmental area of the brain, responsible for hormone secretion and associated with the reward system, requiring surgical intervention.

The treatment was tested in vivo on four rhesus macaques deliberately made alcohol-dependent. Initially consuming the equivalent of nine drinks per day for a human, their alcohol consumption was reduced by 50% after the first withdrawal cycle compared to the control group. Consumption continued to decrease with subsequent cycles, reaching a 90% reduction after one year. The monkeys appeared to voluntarily avoid alcohol and prefer water, suggesting a learned aversion. Blood alcohol levels neared zero, and post-mortem brain examinations revealed reset dopaminergic circuits and normalized hormone levels.

However, it’s important to note that the dopaminergic pathway plays a significant role in movement control and other behaviors. During experiments, treated animals drank less water and consumed only about 20% of sweetened water compared to the control group. The treatment also resulted in an 18% body weight loss. The true behavioral implications of these effects require further investigation.

Nonetheless, the treatment comes with considerable risks due to its invasive nature and potential side effects inherent in gene therapies (such as severe immune reactions, infections, and hemorrhages). Additionally, the inability to reverse the effects of gene therapy, unlike standard drug treatments, could exacerbate potential side effects. Given these risks, the newly developed treatment could only be considered as a last resort.