Anti-cancer drug may be used to treat autism

By ANNA CHEN | March 29, 2018

Researchers at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, led by Zhen Yan, professor in the Department of Physiology and Biophysics, discovered a promising treatment method for the effects caused by autism spectrum disorder (ASD).

Autism spectrum disorder is a developmental disorder that affects one in 68 children. From minor communication issues to the inability to speak at all, ASD manifests in a variety of symptoms. 

Individuals on the spectrum may experience repetitive behaviors, difficulty expressing themselves and forming relationships with other people, and understanding abstract concepts.

Despite years of research, there is still no available treatment for ASD-caused symptoms.

Yan’s previous research in 2015 had revealed that a major contributor of the social symptoms common to ASD patients is the loss of the Shank 3 gene, which disrupts the function of a receptor that regulates neuronal communication and thus cognition and emotion.

Shank 3, however, is not the only gene whose function is lost in ASD patients. ASD is actually caused by hundreds of genetic mutations. The biggest challenge over the years has been determining how to target all the lost gene functions at one time.

Past scientific research had shed light on the nature of the gene losses and mutations that occur in ASD patients. These mutations occur as a result of malfunctioning chromatin remodeling factors. 

Chromatin remodeling factors are proteins that regulate gene expression, often by condensing DNA and preventing transcription factors from expressing the genes or loosening DNA and allowing transcription factors access to the genes.

As a result, the Yan lab decided next to target a protein called histone deacetylase (HDAC), specifically HDAC2, which was previously found to be present in abnormally high levels in ASD individuals. 

HDAC activity packs chromatin very tightly, preventing gene expression of certain genes known to be ASD risk factors, such as Shank 3.

Since some cancers also involve abnormal gene expression, Yan and her team decided to test the anti-cancer drug romidepsin (an HDAC2 inhibitor which lowers HDAC2 levels and allows for normal gene expression) to determine its potential in treating ASD-associated social deficits.

Tested in an autism mouse model deficient in Shank 3 and other genes, a small dose of romidepsin administered in a three-day treatment was found to reverse social deficits in the mice for three weeks. 

The length of the period spans the juvenile to adolescent stages of the mouse’s development, a period of time critical to developing communication skills.

Upon running genome-wide screening, Yan and her team found that of the 200 genes suppressed in the autism mouse model, more than half of them had been restored.

“Autism involves the loss of so many genes... To rescue the social deficits, a compound has to affect a number of genes that are involved in neuronal communication,” Yan said in a press release. 

Yan is excited about the implications of this new discovery. Since romidepsin is potent and allows for widespread HDAC2 inhibition, this anti-cancer drug may be one promising solution for the treatment of ASD-associated symptoms.

To delve deeper into the findings, Yan founded a start-up company called ASDDR, through which Yan and her colleagues will continue their work on ASD. 

Funded by a grant from the National Institutes of Health, she hopes that she and her team will get closer and closer to developing an effective therapeutic agent for autism.

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