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Cancer Drug Seen to Reverse Autism Spectrum Symptoms

Zhen Yan

Zhen Yan (Sandy Kicman, University at Buffalo)

13 March 2018. Small doses of a drug for blood-related cancers are shown in lab mice to reverse social symptoms often found in children with autism spectrum disorder, a condition characterized by limited social activity. Findings from the study by researchers at University at Buffalo in New York appear in yesterday’s issue of the journal Nature Neuroscience (paid subscription required).

The team led by neuroscience and physiology professor Zhen Yan is examining treatments for autism spectrum disorder symptoms. Autism spectrum disorder is a collection of neurodevelopmental conditions marked by communication difficulties and impaired social interaction, as well as repetitive and stereotyped patterns of behavior. Some 1 in 68 children have autism spectrum disorder, according to Centers for Disease Control and Prevention, with males 5 times more likely to have the disorder than females. Classic autism is considered the most severe form of the syndrome.

Yan and colleagues are exploring ways to reverse the effects of a non-functioning gene called Shank3, considered a high risk factor of autism spectrum disorder. Proteins coded by Shank3 enable the functioning of synapses, the junctions of nerve cells responsible for signaling, with some 43 mutations in the Shank3 gene found in people with autism spectrum disorder. These mutations prevent or disrupt production of Shank3 proteins.

In earlier work, Yan’s group found the lack of Shank3 proteins disrupts receptors in the brain needed for normal nerve cell functioning. These N-methyl D-aspartate or NMDA receptors help keep synapses flexible, which affects memory, learning, and development of the central nervous system, as well as lack of social interaction common in autism spectrum disorder. To make up for this lack of key proteins, the researchers tried a solution that changes genetic material in cells called chromatin that forms chromosomes. To accomplish this remodeling task, they needed an agent that could modify the chromatin, allowing for normal expression of genes in those cells.

The Buffalo team turned to a currently approved cancer drug known to modify chromatin in cells. That drug, known as romidepsin, treats some types of leukemia and lymphoma by blocking enzymes that stop basic proteins in the formulation of DNA called histones. As a cancer drug, romidepsin disrupts histones and thus the formation of DNA that supports leukemia or lymphoma cells.

In the case of autism spectrum disorder, romidepsin — in a class of drugs known as histone deacetylase or HDAC inhibitors — frees up the chromatin in cells allowing Shank3 genes to function normally. As Yan explains in a university statement, “The HDAC inhibitor loosens up the densely packed chromatin so that the transcriptional machinery gains access to the promoter area of the genes; thus they can be expressed.”

The researchers tested their hypothesis in lab mice deficient in the Shank3 gene, and who failed to display normal social activity. The team gave the mice minute doses of romidepsin for 3 days, which resulted in restored functioning of NMDA receptors as well as proteins providing flexibility to synapses in the mice brains, and according to the authors, “rescued their social deficits.” In addition, the effects of these treatments lasted 3 weeks, which the researchers say is equivalent to several years in the human lifetime.

Yan founded the company ASDDR LLC in Amherst, New York to commercialize her lab’s findings. In June 2017, ASDDR received a 2-year, $777,000 Small Business Technology Transfer award from National Institute of Mental Health, part of National Institutes of Health. That grant funds further preclinical research on romidepsin as a treatment for autism spectrum disorder.

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