Summary: Researchers report that a very low dose of the anti-cancer drug romidepsin reduced social deficits in animal models of autism.
Source: University at Buffalo.
Social difficulties are among the most disabling features of autism spectrum disorder (ASD), and currently no approved treatment directly targets these core symptoms. New research from the University at Buffalo provides the first evidence that a single compound can alleviate autism-like social deficits by adjusting the expression of multiple genes involved in the condition.
Published in Nature Neuroscience, the study shows that a brief, low-dose course of romidepsin—an FDA-approved anti-cancer drug—produced a sustained improvement in social behavior in multiple animal models of ASD. The treatment reversed social deficits after only three days of administration and maintained the benefit for weeks.
The experiments focused on mice lacking the Shank3 gene, a well-established genetic risk factor for ASD. A short romidepsin treatment restored normal social preference in these mice for a period of roughly three weeks, a span that corresponds to a key developmental window from juvenile to late adolescent stages. Translating this to humans suggests the potential for lasting effects from targeted, time-limited interventions.
Strong, lasting effect without obvious side effects
“We identified a small-molecule compound that produces a profound, long-lasting improvement in autism-like social deficits without apparent side effects,” said Zhen Yan, PhD, professor in the Department of Physiology and Biophysics at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, and senior author of the paper. Many existing psychiatric medications have not demonstrated efficacy for this core symptom of ASD.
This study extends Yan’s earlier work showing that loss of Shank3 disrupts neuronal communication by impairing NMDA receptor function, a receptor crucial for learning, memory, and social behavior. The new results indicate that romidepsin restores disrupted gene expression and neuronal function through epigenetic mechanisms—changes in gene activity caused by factors other than alterations in the DNA sequence itself. Genetic studies in humans have previously implicated epigenetic dysregulation as a contributor to ASD.
To support further development, Yan has co-founded a startup, ASDDR, which received a Small Business Technology Transfer grant from the National Institutes of Health to pursue translation of these findings.
Targeting epigenetics in ASD
Many risk mutations linked to autism affect chromatin remodeling factors—proteins that alter the structure of chromatin, the complex of DNA and proteins that form chromosomes. Because chromatin remodeling controls which genes are accessible for transcription, drugs that influence these mechanisms can broadly modulate gene networks implicated in ASD.
“There is considerable overlap between genes associated with autism and those involved in cancer, particularly chromatin remodelers,” Yan explained. “That overlap supports repurposing certain epigenetic drugs used in oncology as potential targeted treatments for autism.”
Rather than attempting to correct a single gene, the research team focused on histone modifiers, enzymes that change how DNA is packaged around histone proteins and thereby regulate gene expression. Because autism often involves dysregulation of many genes that govern neuronal signaling, a histone-targeting approach can adjust multiple disease-relevant genes simultaneously.
Loosening chromatin to restore gene expression
The team concentrated on histone deacetylases (HDACs), a family of enzymes that tighten chromatin structure and suppress gene expression. In the Shank3-deficient autism model, HDAC2 levels were abnormally elevated, which condensed chromatin and blocked access to key promoters needed for normal gene activity. This suppression contributed to the observed social deficits.
Romidepsin is a potent HDAC inhibitor. In the treated animals, romidepsin reduced HDAC2’s repressive effects, loosening chromatin and permitting transcriptional machinery to activate genes involved in neuronal communication. Genome-wide screening conducted at UB’s Genomics and Bioinformatics Core found that romidepsin restored expression of the majority of more than 200 genes that had been suppressed in the autism model.
“The ability to adjust a network of genes that are key autism risk factors likely explains the strong and lasting benefit we observed,” Yan said. The team plans to continue searching for and developing therapeutic agents that safely target these epigenetic mechanisms in ASD.
Co-authors include Luye Qin, PhD; Kaijie Ma; Zi-Jun Wang, PhD; Emmanuel Matas, PhD; Jing Wei, PhD; and Zihua Hu, PhD, representing researchers in the Department of Physiology and Biophysics and the New York State Center of Excellence in Bioinformatics and Life Sciences at the University at Buffalo.
Funding: The study was supported by the Nancy Lurie Marks Foundation and the National Institutes of Health.
Source: Ellen Goldbaum, University at Buffalo. Publisher: Organized by NeuroscienceNews.com. Image source: illustrative image credited to NeuroscienceNews.com. Original research published in Nature Neuroscience.
Suggested citation formats: MLA, APA, Chicago (University at Buffalo, 2018). Provide full journal citation when referencing the Nature Neuroscience article.