Gene interaction analysis predicts existing drugs that could be repurposed for autism

There is no shortage of research on treatments for autism spectrum disorder, or ASD, a wide-ranging neurodevelopmental condition marked by impaired social communication. Yet, while dozens of potential therapeutic targets are under investigation, individuals with ASD currently are treated with Band-Aid solutions for symptoms rather than for the condition itself. 

But by using a series of analyses to predict how gene protein products interact, researchers Elise Koch, Ph.D. and Ditte Demontis, Ph.D., from Norway’s University of Oslo have homed in on existing drugs that they believe warrant testing in individuals with ASD. The results of their study, published Monday in Frontiers of Pharmacology, indicate four meds to assess: anti-diarrheal loperamide, dopamine D2 receptor agonist bromocriptine, the female hormone progesterone and the progestin birth control pill drospirenone. 

To conduct their analysis, the researchers first identified ASD genes using two different sources: a sequencing study that involved 12,000 people with autism and the most recent large-scale genomewide association study, which included samples from around 18,400 individuals with ASD and another 28,000 controls. In total, they analyzed 207 genes within the so-called ASD network.  

The researchers then ran the genes through the Drug Gene Interaction Database, an open-source repository of information on drug-gene interactions and the “druggable genome.” The database returned interactions between 439 approved drugs and 68 genes in the ASD network. They then used the Broad Institute’s Connectivity Map database to evaluate how the drugs altered gene expression. After a round of analysis with MetaXcan, another open-source tool that is used to predict gene expression levels, they looked for negative correlations between drug-induced gene changes and gene changes caused by ASD. Negative correlations, they reasoned, would indicate that the drug could theoretically reverse ASD-associated gene changes.  

Notably, all four of the pharmaceuticals that were predicted to act against ASD gene changes work via mechanisms with established links to the condition. In the case of progesterone and drospirenone, studies have shown a positive correlation between testosterone levels and social communication challenges in ASD. Researchers have also postulated that low maternal progesterone levels during pregnancy could predict ASD development. And bromocriptine, the dopamine receptor agonist, was in fact studied as a potential ASD therapy in the early 1990s and showed some encouraging improvement in attention symptoms.  

But it was loperamide, better known by its brand name Imodium, that appeared to have the greatest potential to reverse the changes ASD genes caused. This likely has to do with its activity as a mu-opioid receptor agonist. While drugs affecting the opioid system are well known for their analgesic properties and impact on the brain’s reward system, they’ve also recently been implicated in modulating social behavior. 

Mice without opioid receptors have behavioral and social changes like those in humans with ASD, and studies have shown that restoring this deficiency can reverse them. A recent clinical case report of an ASD individual whose social functioning improved when he began taking the partial mu-opioid agonist buprenorphine backs up this notion, too.  

While it’s promising that all four drugs identified are acting on pathways that have previously been linked to autism, it’s still much too early to say whether any of them will have enough of an impact on gene expression to improve social communication in people with ASD. Still, the scientists are confident that their findings warrant further investigation and in their paper called for more research to be done.  

“These results require follow-up experiments and finally clinical trials to enable clinical translation,” they wrote.