Researchers from the State University of New York at Buffalo have demonstrated that an anticancer agent called romidepsin, which is a highly potent HDAC inhibitor, can effectively restore social deficits in mouse models of autism. In addition, the beneficial effect of romidepsin lasts for a relatively long period of time.
Published in the online version of the journal Nature Neuroscience on 12 March 2018, the study (Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition) may lead to novel therapies to improve social abilities of patients with autism.
Autism, also referred to as autism spectrum disorder (ASD), is a large group of developmental disorders. Patients with autism may have problems in social interactions and communication and exhibit repetitive behaviors and delayed development. Not only can autism significantly affect the patients' lives but also cause considerable economic consequences. Unfortunately, no effective treatments are available to address social deficits in patients with autism.
Many genes have been linked to the increased risk of developing autism. But it is believed that there are still unknown ones. Recent studies have shown that about 1-2% of individuals with autism are missing a gene called SHANK3
, suggesting SHANK3 as a leading autism candidate gene. The SHANK3 protein is a multifunctional synaptic protein, which is critical for brain development. SHANK3 deficiency has been shown to induce autism-like behavioral deficits in the brain of mice, and SHANK3-deficient mice become a useful organism model for studying the pathogenesis of autism and testing new drugs.
In this work, the researchers demonstrated that "brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks." In Shank3-deficient mice, HDAC2
transcription was upregulated. "Once HDAC2 is upregulated, it diminishes genes that should not be suppressed, and leads to behavioral changes, such as the autism-like social deficits," said Dr Zhen Yan, who is the corresponding author of the study.
HDAC2 (histone deacetylase 2)
is an epigenetic enzyme that belongs to the histone deacetylase family. HDACs play key roles in regulating gene expression. Modulation of gene expression is a necessary event for mammalian brain function.
Collectively, the results suggest that romidepsin has long-lasting effects in alleviating social deficits in Shank3-deficient mice. Additionally, the study highlights "
an epigenetic mechanism underlying social deficits linked to Shank3 deficiency."
Other researchers participating in the study include Luye Qin, Kaijie Ma, Zi-Jun Wang, Zihua Hu, Emmanuel Matas, and Jing Wei from the State University of New York at Buffalo.
Romidepsin is an FDA-approved drug used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). More research is needed to test the efficacy and safety of this anticancer drug in treating autism.