Discovery of Novel Drugs for Autism

Summary The goal of this study is to discover novelmechanism based pharmacological intervention for autisma devastating neurodevelopmental disorder with no treatment currentlyGenetic sequencing has revealed extensive overlap in risk genes for autism and for cancermany of which are chromatin remodeling factors important for transcriptional regulationsuggesting the possibility of repurposing the anti cancer drugs targeting epigenetic enzymes for autism treatmentASDDR LLC and Yan Lab at SUNY Buffalo propose to jointly investigate the hypothesis that histone deacetylaseHDACinhibitors are able to restore the expression of key autism risk factors and induce long lasting rescue of autism like behavioral and synaptic deficitsCombined behavioralbiochemical and electrophysiological approaches will be used to address two specific aimsAimTo discover HDAC inhibitors that can alleviate autism like behavioral deficits in autism mouse modelsYan lab screened a number of drugs and found that a brief treatment with the highly potent and class I specific HDAC inhibitorromidepsinIstodaxan FDA approved anti cancer agentat the very low doseled to dramatic and prolonged rescue of the social deficits in the Shankdeficient mouse model of autismTo determine whether this pharmacological agent can serve as a tool compound for autism drug developmentits therapeutic efficacy and safety will be examined in two different models of autismShankdeficient mice and BTBR miceAimTo identify the molecular targets of HDAC inhibitors as benchmarks for the treatment of autismFor the discovery of effective drugs to treat autismthe molecular pathways on which HDAC inhibitors act to alleviate the autism like behavioral deficits in Shankdeficient mice need to be understoodWe will reveal the potential benchmarksuch as actin regulators and NMDARsas molecular targets of romidepsinThis phase I preclinical study will provide great promise for the discovery of new and effective pharmacological agents to treat the social interaction deficitsa core symptom of autism