A recent study published earlier this month in Nature Medicine, found that gene therapy could be used to treat alcohol use disorder. The treatment significantly reduced alcohol consumption in animal models, even after they were reintroduced to alcohol numerous times. To the outside eye, this may seem an unexpected use—gene therapies are typically used to target genetic diseases. My interest was piqued. What inspired this novel application, and what are the broader implications for treating other addiction disorders? 

To seek answers, I spoke with the co-principal investigator of the study, Dr. Krystof Bankiewicz, professor of Neurological Surgery and Director of the Brain Health and Performance Center at Ohio State University. Bankiewicz explained that his work on gene therapy for alcohol addiction originates from his earlier work on Parkinson’s disease and the role of glial-derived neurotrophic factor (hGDNF), a protein encoded by the GDNF gene. 

“The origins of this study come from the work we’ve conducted to bring gene therapy to Parkinson's patients,” says Bankiewicz. “It took [me and many investigators] a couple of decades to really understand what GDNF is doing in the dopaminergic system.” 

The exact relationship between dopamine and Parkinson’s is unclear, but there are known connections between the two. For people with addiction, dopamine plays a central role in the human rewards system.

“With addictive behaviors, that reward pathway is down-regulated because it’s being overstimulated by stimulants, [such as] alcohol, cocaine, and opiates. There are a number of ways being utilized to help patients with addiction, but they’re not really addressing the fundamental mechanism,” says Bankiewicz.

Central to this study is the therapeutic molecule AAV2-hGDNF, which Bankiewicz has already used to treat Parkinson's patients. But formulating the drug is only half the challenge. Gene therapies require precise delivery to the target area, in this case, within the brain. Bankiewicz points out that the neural pathway controlling motor function in Parkinson’s patients and the reward system affected in people with addiction are only millimeters apart. “You really have to know how to target this region precisely,” Bankiewicz says.

To precisely target the right reward pathway, Bankiewicz relied on his earlier work treating children with dopamine deficiency. Bankiewicz believes this condition's target is the same for treating alcohol use disorder. By combining the tools and therapeutic he developed to treat Parknson’s and the location to treat dopamine deficiency, Bankiewicz realized there might be an opportunity to treat severe addiction with gene therapy. 

Bankiewicz and his team partnered with Dr. Kathleen Grant, chief and Professor of Behavioral Neuroscience at the Oregon National Primate Research Center, which had the required capacity for this study. It's important to mention the ethical considerations when investigating addiction in animal models. To conduct the study, the teams first had to addict rhesus monkeys to alcohol. Unfortunately, this is still the best method for studying addiction at this level. After establishing a baseline addiction, the team surgically delivered the gene therapy directly into the brain. To find their target, Bankiewicz and his team used continuous MRI scanning to reach their target precisely.

“I think we’ve been pretty clever in terms of understanding neural projections and how these viral [delivery] particles travel along. You will never be able to achieve [that level of precision] with IV administration,” says Bankiewicz. “Because we’re imaging all the time, we know how to avoid blood vessels with incredible precision and how to get the therapeutic to the right place.”

This technique ensures both safety and efficiency in delivery—an imperative for any therapy seeking to progress to human trials. However, delivery isn't the only concern—using gene therapy to treat addiction may have broader implications in the mind. In addition to alcohol cessation, the monkeys treated with gene therapy also stopped other unhealthy habits such as over-eating and high-sugar intake. While this sounds like a positive result, it comes very close—and possibly even crosses the line—to altering someone's personality. 

“The therapeutic looks like it’s rewiring the reward pathway to the extent that those cravings are gone. But what’s left? I don’t know. We did not test these animals in terms of their cognitive abilities and other functions,” Bankiewicz explains. For Bankiewicz, this unknowing stops the move to human trials in its tracks. 

“I have very little appetite for moving forward unless I can turn this therapeutic off,” he says firmly. It’s one thing to give Parkinson’s patients the ability to walk or drive or play tennis, but it's another to alter someone's personality in such a permanent way. “This is different. It gets into human mind control, in a sense,” Bankiewicz says.

Until a mechanism to control the gene therapy's effects is developed, animal model trials will continue before these therapies can be applied to human addiction disorders. 

However, Bankiewicz's work on Parkinson's disease using the same therapeutic is progressing significantly. Soon, the team will begin large-scale international trials. Bankiewicz is quite optimistic, saying, “The data we’ve been getting for two years from the last group of patients—I’ve never seen anything like it.” The goal is to advance the drug through approvals and bring it to patients around the world. Bankiewicz’s team isn’t alone in this endeavor, and they have partnered with Bayer for the scaling and commercialization process. 

I, for one, will be keeping a close eye on the results of these Parkinson’s trials and for the next phase of Bankiewicz's work with Kathleen Grant on alcohol and other addiction disorders. The teams are developing potentially life-changing treatments for some of the most difficult-to-address societal burdens, namely the impact of addiction on a person’s life, family, and community. If we can achieve this without altering a person’s mind, we will have achieved something monumental. 

The implications of this study resonate deeply in a nation where an estimated 28.6 million adults and 894,000 adolescents had AUD in 2021, according to the National Survey on Drug Use and Health. With 140,000 deaths per year attributed to AUD, the search for an effective treatment is more than a scientific endeavor—it is a human imperative. The ray of hope offered by this research may someday illuminate a path for many, leading them out of the shadows and into a life free from the chains of addiction.