Romidepsin, a histone deacetylase (HDAC) inhibitor and FDA-approved lymphoma drug, reversed the social deficits of autism spectrum disorder (ASD) in a mouse model of the condition.

Senior author Zhen Yan, professor of physiology and biophysics at the University at Buffalo Jacobs School of Medicine and Biomedical Science, told BioWorld that the work marks the first identification of "a small-molecule compound that can have a prolonged effect on the social deficits of autism."

Yan and her team published their results in the March 12, 2018, online issue of Nature Neuroscience.

Autism spectrum disorder is a condition that is as common as it is complex. The spectrum is an extremely broad one – high-functioning individuals may be able to live independently, while those who are most severely afflicted cannot speak or take care of themselves.

What individuals with ASD have in common, though – the "core symptoms" – are social deficits. Those deficits can include a lack of ability to understand others' perspective, as well as communication deficits, impaired ability to regulate their own emotions, and deficits in social reciprocity.

FDA-approved drugs for ASD, Yan said, are "basically just for managing irritability. They do not affect the core symptoms of autism."

The physiology of autism, too, is complex and incompletely understood. But one thing that is clear is that there are broad changes in the connectivity of neurons to each other, and in the synapses that are the point of contact between neurons.

Finally, the genetics of ASD are – wait for it – complex. But "the most prominent mutations occur on those genes that are involved in chromatin remodeling and epigenetics," Yan said.

In the work now published in Nature Neuroscience, Yan and her team used mice lacking one copy of the Shank3 gene. Human genetic studies have shown that equivalent mutations are the cause of 1 percent to 2 percent of ASD cases.

"It's not a huge population," Yan acknowledged. "But it is one of the most prevalent monogenic causes for autism."

The scientists tested romidepsin, other HDAC inhibitors, and other neuropsychiatric drugs for their ability to reverse social deficits in the animals. They showed that daily injections of low doses of romidepsin – about 5 percent of that used in cancer treatment – for three days were sufficient to increase acetylation of Shank3, and restore expression of the majority of the more than 200 genes whose expression is reduced by the partial loss of Shank3.

In mice that were a few weeks of age – the equivalent of human adolescence – the same three-day treatment led to improvements in social behavior. Mice with only one copy of Shank3 usually have deficits in social interaction and prefer interacting with an inanimate object over another mouse. Romidepsin reversed those behaviors, making the animals more similar to wild-type mice in their behaviors.

The effects were specific to romidepsin – treatment with selective serotonin reuptake inhibitors, which treat depression, were ineffective, as were treatment with the FDA-approved autism medications Risperdal and Abilify.

Treatment with a more broad-spectrum HDAC inhibitor, trichostatin A, or with the less potent HDAC inhibitor valproic acid, was effective, but the effects of both drugs wore off much more quickly than those of romidepsin. In contrast, the effects of romidepsin lasted for weeks – in line with the reports of long-term effects of romidepsin in humans, where it can affect gene expression for more than a year.

Yan and her team are currently testing more compounds that work on different aspects of epigenetic regulation. Yan is the founder of startup ASDDR LLC, which has set up shop in U Buffalo's incubator with the goal of discovering novel mechanism-based interventions for autism.

"I think down the road, maybe there are more HDAC inhibitors that are more permeable... that are more effective," Yan said. "Romidepsin is pretty promising in the young animals, but it doesn't work in adults."

Repeated injections were also ineffective, though Yan said that "is probably because the animals have already reached adulthood when we test the second round."

Overall, she said, it will likely take more than one drug to lead to significant improvements in ASD. It is "a very complicated disorder," she said, "and it's probably difficult to find a magic bullet that will cure everything."

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