Researchers headed by a team at the University of Oslo have identified a drug that is currently used to treat diarrhea, as a potential therapeutic candidate for core symptoms of autism spectrum disorder (ASD). The investigators constructed a computer model of the network of proteins associated with ASD, and their interactions, and looked at how different drugs impacted proteins in the network. They identified a number of candidates that would be expected to counteract the biological process underlying ASD, and of these, the commonly used anti-diarrheal drug, loperamide, was the most promising.

The researchers also developed a hypothesis about how loperamide might work to counter some of the social interaction and communication difficulties that are associated with ASD. Elise Koch, PhD, is lead author of the team’s paper published in Frontiers in Psychiatry,  titled “Drug repurposing candidates to treat core symptoms in autism spectrum disorder.” In their report, the team concluded, “Based on our bioinformatics analyses of ASD genetics, we shortlist potential drug repurposing candidates that warrant clinical translation to treat ASD-specific symptoms.”

The main core symptoms associated with ASD are social communication deficits, and restrictive behaviors, which are often accompanied by other psychiatric issues, from sleep problems, to anxiety or depression, attention deficit hyperactivity disorder (ADHD), aggression, and irritability, the authors noted.

“There are no medications currently approved for the treatment of social communication deficits, the main symptom in ASD,” said Koch. “However, most adults and about half of children and adolescents with ASD are treated with antipsychotic drugs, which have serious side effects or lack efficacy in ASD.” In fact, up to 57% of children and more than 65% of adults with ASD are treated using antipsychotics, the investigators continued. ADHD medications are used by up to 45% of children and 15% of adults, and antidepressants are used by up to 32% of children and 43% of adults. “Currently, there are only two medications approved by the FDA for targeting ASD-associated irritability, the antipsychotics risperidone and aripiprazole,” the researchers commented. And in Europe, there are no drugs approved for treating ASD-associated symptoms, though guidelines do support the use of risperidone and aripiprazole. But drugs such as antipsychotics can have “considerable limitations,” the investigators continued, including serious side effects such as antipsychotic-induced weight gain. “The clinical and genetic heterogeneity of ASD complicates the development of pharmacologic treatments, which necessitates the use of new approaches to identify novel treatment options for ASD,” they stated.

In an effort to find a new way to treat ASD, the researchers explored the potential to repurpose existing drugs. This approach can have multiple benefits, as there is often extensive knowledge about existing drugs in terms of their safety, side effects, and their targets.

For their study, the investigators developed a computer-based protein interaction network that included proteins associated with ASD. Such networks encompass proteins and the complex interactions between them. It is important to account for this complexity when studying biological systems, as affecting one protein can often have knock-on effects elsewhere. “To identify potential drugs for repurposing to effectively treat ASD core symptoms, we studied ASD risk genes within networks of protein-protein interactions of gene products,” they noted.

“First, we defined an ASD network via network-based methods, and studied the genes in this network in relation to interactions with approved drugs,” the scientists explained. “Then, we selected drug repurposing candidates that could change ASD-associated gene expression perturbations and identified various drugs that may potentially be repurposable to address the core symptoms in ASD. This was done by analyses of drug-induced versus ASD-associated gene expression, where opposite gene expression perturbations in drug versus ASD indicate that the drug could counteract ASD-associated perturbations.”

By investigating existing drugs and their interaction with proteins in the network, the team identified several candidates that counteract the biological process underlying ASD. The most promising drug, loperamide, is commonly used for treating diarrhea. Loperamide binds to and activates the μ-opioid receptor, which is normally the target of opioid drugs, such as morphine. But along with the effects that might be expected from an opioid drug, such as pain relief, the μ-opioid receptor also affects social behavior. “… the μ-opioid receptors do not only modulate analgesic and rewarding properties of opioids, but they also play a critical role in modulating social behavior in both humans and animals,” the authors wrote.

In previous studies, genetically engineered mice that lack the μ-opioid receptor demonstrated social deficits similar to those seen in ASD. Interestingly, drugs that activate the μ-opioid receptor helped to restore social behaviors. These previous results in mice highlight the possibility that loperamide, or other drugs that target the μ-opioid receptor, may represent a new way to treat the social symptoms present in ASD. “Thus, the identification of loperamide as a drug repurposing candidate for ASD is consistent with its potential to modulate social behavior in ASD,” the team continued. “In addition, it may have favorable gastrointestinal effects in individuals with ASD, as gastrointestinal symptoms are common in ASD.”

While further studies will be required to validate the researchers’ findings, they concluded, “In the present study, we have identified existing drugs that could potentially be used for repurposing to address core symptoms in ASD … These results require follow-up experiments and finally clinical trials to enable clinical translation.”

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