Social Deficits of Autism Reversed By Epigenetic Drug

It is estimated that 1 in 59 children in the United States fall somewhere on the autism spectrum. Autism spectrum disorder  (ASD) is a developmental disorder that affects the nervous system and is characterized by challenges with speech, social skills and communication.  Many factors can determine a child’s predisposition to developing autism, such as genetic mutations during brain development, chemical imbalance, and certain genetic disorders like tuberous sclerosis  and fragile X syndrome.

Autism has been an incredibly difficult disease to treat because of the many different risk factors and genes associated with the disease, and so far a cure has not been discovered. But in a recent study published in Nature Neuroscience, a group of scientists from the University of Buffalo found that epigenetics may provide insight into unlocking a potential cure for the intense behavioral symptoms associated with ASD.

Dr. Zhen Yan, a professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, and her research team investigated a gene called Shank 3, which plays an important role in the proper functioning of synapses in the brains of mice and humans, and is a high-risk target for developing ASD.

Dr. Yan previously discovered that a mutation to the Shank 3 gene leads to a dysregulation of emotional and cognitive response, hindering social capabilities, which is the central theme for ASD.

In this study, Dr. Yan explains the mutations that cause ASD stem from a high level of gene suppression caused by dysregulation in epigenetic mechanisms that modify chromatin structure, known as chromatin remodeling factors. The challenge would be pinpointing exactly which chromatin remodelers had the most impact on gene expression in genes linked neuronal development, and developing a treatment to target them all.

Since many genes are involved in ASD development, the key to treating the social deficits was to focus on histone modifications and how they effect and alter gene expression in the autism model. Autism is affiliated with extremely high levels of histone deacetylase 2 (HDAC2) which severely tightens the chromatin, resulting in gene suppression.

Dr. Yan believes this is the reason that people suffering from autism experience social abnormalities: “Once HDAC2 is upregulated, it diminishes genes that should not be suppressed, and leads to behavioral changes, such as the autism-like social deficits.”

The team turned to epigenetic anti-cancer drug called romidepsin, which is highly potent HDAC inhibitor. They treated mice deficient in the Shank 3 gene with a low dose of the drug for three days and found that gene function and expression were restored, and the social deficits were completely reversed. The drug successfully diminished the effects of HDAC2, which loosened the chromatin, allowing transcriptional mechanisms to restore gene expression.

The drug’s effect lasted about three weeks, which is the period of juvenility to late adolescence in mice. This equates to several years when compared to human development – a period of time that is crucial to the development of communication and social skills.

Upon further genome-wide screening, the team found that treatment with romidepsin was extensively effective at restoring the function to more than 200 genes that were previously silenced by autism. This discovery is critical in providing hope to combat the social shortfalls of AS in humans.

“We have discovered a small molecule compound that shows a profound and prolonged effect on autism-like social deficits without obvious side effects; while many currently used compounds for treating a variety of psychiatric diseases have failed to exhibit the therapeutic efficacy for this core symptom of autism” said Dr. Yan, who hopes that the success of the drug in this study can provide a simple treatment early on in human development to help reverse Shank3 deficiency and alleviate the social difficulties of autism.

Source: Zhen Yan et. al. (2018) Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nature Neuroscience 21, 564–575.

Reference: University at Buffalo. “Autism’s social deficits are reversed by an anti-cancer drug.” University at Buffalo News Center, 12 March 2018. Web.