The inability to relate to others is one of the most dramatic consequences for patients with autism spectrum disorder . And, currently, there is no treatment for this symptom. Fortunately, new research by scientists at the University of Buffalo (USA) reveals the first evidence that it is possible to use a single drug to alleviate behavioral symptoms, as it targets sets of genes involved in the illness.
The research, published in the journal Nature Neuroscience, showed that brief treatment with a very low dose of romidepsin, an FDA-approved cancer drug , steadily restored social deficits in mice with autism.
The three-day treatment reversed social skills problems in a gene called Shank 3, a major risk factor for autism spectrum disorder. This effect lasted three weeks, spanning from the juvenile period to the late adolescence of rodents, a critical developmental stage for social and communication skills, the equivalent of several years in humans, suggesting that the effects of similar treatment could be long-lasting , the researchers say.
“We have discovered a compound that has a profound and long-lasting effect on autism-like social deficits with no apparent side effects,” says Zhen Yan, leader of the work.
The study builds on earlier research from 2015 that revealed how loss of Shank 3 disrupts neural communications by affecting the function of the NMDA (N-methyl-D-aspartate) receptor, a critical player in the regulation of cognition and the emotion.
To continue these promising findings, Yan founded a startup company called ASDDR, which received a grant from the National Institutes of Health for more than $ 770,000.
In the new research, the scientists found that they could reverse these social deficits with a very low dose of romidepsin , restoring gene expression and function using an epigenetic mechanism, where genetic changes are caused by influences other than DNA sequences.
“Autism involves the loss of many genes,” explained Yan. “To rescue social deficits, a compound has to affect a series of genes that are involved in neuronal communication.”
To do this, the team turned to a type of chromatin remodeler, histone-modifying enzymes that help organize genetic material in the nucleus (so gene expression can be regulated). Since many genes are altered in autism, scientists were convinced that a histone modifier could be effective.
The rescue effect on gene expression was generalized . When Yan and his team conducted a genomic scan, they found that romidepsin restored most of the more than 200 genes that were deleted in the autistic animal model they used in the experiment.
“The advantage of being able to adjust a set of genes identified as key risk factors for autism could explain the strong and long-lasting efficacy of this therapeutic agent for autism,” concludes Yan.
Reference: Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition, Nature Neuroscience (2018). nature.com/articles/doi:10.1038/s41593-018-0110-8
