Discovery of Novel Drugs for Autism

Period of Performance: 06/29/2017 - 05/31/2018

$388K

Phase 1 STTR

Recipient Firm

Asddr, LLC
Amherst, NY 14228
Principal Investigator

Abstract

Summary The goal of this study is to discover novel, mechanism-based pharmacological intervention for autism, a devastating neurodevelopmental disorder with no treatment currently. Genetic sequencing has revealed extensive overlap in risk genes for autism and for cancer, many of which are chromatin remodeling factors important for transcriptional regulation, suggesting the possibility of repurposing the anti-cancer drugs targeting epigenetic enzymes for autism treatment. ASDDR LLC and Yan Lab at SUNY-Buffalo propose to jointly investigate the hypothesis that histone deacetylase (HDAC) inhibitors are able to restore the expression of key autism risk factors and induce long-lasting rescue of autism-like behavioral and synaptic deficits. Combined behavioral, biochemical and electrophysiological approaches will be used to address two specific aims. Aim 1. To discover HDAC inhibitors that can alleviate autism-like behavioral deficits in autism mouse models. Yan lab screened a number of drugs and found that a brief treatment with the highly potent and class I-specific HDAC inhibitor, romidepsin (Istodax, an FDA-approved anti-cancer agent) at the very low dose, led to dramatic and prolonged rescue of the social deficits in the Shank3-deficient mouse model of autism. To determine whether this pharmacological agent can serve as a tool compound for autism drug development, its therapeutic efficacy and safety will be examined in two different models of autism, Shank3-deficient mice and BTBR mice. Aim 2. To identify the molecular targets of HDAC inhibitors as benchmarks for the treatment of autism. For the discovery of effective drugs to treat autism, the molecular pathways on which HDAC inhibitors act to alleviate the autism-like behavioral deficits in Shank3-deficient mice need to be understood. We will reveal the potential benchmark, such as actin regulators and NMDARs, as molecular targets of romidepsin. This phase I preclinical study will provide great promise for the discovery of new and effective pharmacological agents to treat the social interaction deficits, a core symptom of autism.