Researchers Use CRISPR to Reset Anxiety, Alcohol Use Disorder
Researchers at the University of Illinois at Chicago have uncovered the possibility of utilizing gene editing to reverse a cause of anxiety and alcohol use disorder (AUD). The study, published by Science Advances, provides a new approach to a disorder that affects 15 million U.S. adults.
The gene-editing treatment would be effective in patients who began abusing alcohol at an early age, which impairs normal epigenetic and transcription changes associated with brain maturity. This disruption in development is linked to AUD, anxiety and various other psychiatric disorders that can persist through adulthood.
One of the changes that are decreased with early alcohol consumption is the activity-regulated cytoskeleton-associated (Arc) gene expression, in the brain’s amygdala. The arc protein is critical for coordinating synaptic plasticity, such as long-term memory. Arc activity also regulates non-selective histone deacetylase (HDAC), which is important for cognitive function.
Using CRISPR-dCas9, the arc gene activity was able to be evaluated and upregulated to increase histone acetylation. The Cas9 technology was chosen for the ability to easily change specific epigenetic marks, without cutting genetic material or introducing opportunities for error.
With increased histone acetylation of the arc gene, AUD and anxiety decreased in rat experiments.
Subhash Pandey, a senior author of the study, Joseph A. Flaherty Endowed Professor of Psychiatry and director of the Center for Alcohol Research in Epigenetics at UIC, commented on the findings.
"Early binge drinking can have long-lasting and significant effects on the brain, and the results of this study offer evidence that gene editing is a potential antidote to these effects, offering a kind of factory reset for the brain, if you will."
Historically, treating addictions that began early in life is very difficult. This difficulty was echoed by Anthony Tennyson, co-founder of Awakn Life Sciences, in a previous interview for BioSpace.
“There are few effective treatments for addiction that address its root causes," Tennyson said.
Tennyson has a different approach to treating addictions. Awakn combines psychotherapy and psychedelics to treat addiction at its core, instead of just treating the symptoms. For alcohol use disorder, the company uses MDMA (methylenedioxymethamphetamine).
For the scientists at UIL, the method was different, but the end goal was the same. The study included the use of anesthetized adult rats and dCas9 modified lentiviruses. The viruses were modified using dCas9 to increase arc gene activity. The virus was infused directly into the rat brains, and behavior was observed after one week of recovery.
Behavioral tests included an ethanol two-bottle choice drinking paradigm, a sucrose 2BC drinking paradigm, an EPM exploration test and a light-dark box exploration test. These tests show how the rats respond to anxiety-inducing stimuli and drinking preferences when given options. After humane sacrifice, the rats’ amygdala were examined using a ChIP assay to examine genome proteome linkages, real-time PCR, a 3C real-time PCR, and immunofluorescent staining.
The research is funded through grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Department of Veterans Affairs Senior Research Career Scientist Award. The funds were given to support the exploration of additional treatment options for those with AUD or anxiety, as current options are limited to therapy and Alcoholics Anonymous support groups, along with medications that modulate alcoholic dependence or anxiety symptoms. The research conducted by the University of Illinois Chicago is a treatment that would reverse the effects stemming from early alcohol abuse.