Chapter 9 - Inhibition of lysine-specific demethylase 1 enzyme activity by TAK-418 as a novel therapy for autism

Abstract

Phenotypic heterogeneity is a hurdle in developing therapeutic drugs for autism spectrum disorder (ASD). Here we propose an epigenetic approach through the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity for recovering global gene expression changes occurred in the disease state. It was difficult to specifically inhibit LSD1 enzyme activity with avoiding the risk of hematotoxicity that is caused by coinciding disruption of LSD1-cofactor complex. We identified TAK-418, a clinical candidate of LSD1 enzyme activity-specific inhibitor with superior hematological safety profile through the lack of impacts on the LSD1-cofactor complex. Although dysregulation patterns in gene expression were different across various animal models of ASD, TAK-418 counteracted the dysregulated gene expression and ameliorated ASD-like behaviors. TAK-418 may restore global homeostasis in gene expression in response to each disease state, rather than modulate specific biological/functional pathways. TAK-418 warrants further investigation as a novel therapeutic agent for neurodevelopmental disorders.