AST-001-induced therapeutic effects via miRNA modulation of key genes in Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by social and communication impairments, repetitive behaviours, and cognitive and sensory challenges, with genetic factors estimated to contribute 50-60% to ASD risk. This study investigates the therapeutic potential of AST-001, an L-serine derivative, in modulating ASD-related gene expression via miRNA regulation using a valproic acid (VPA)-induced mouse model of ASD. AST-001 treatment recovered the expression of several ASD-related genes in the midbrain, including Discs large MAGUK scaffold protein 4 (DLG4), and Paired Box 5 (PAX5), which are essential for dopaminergic (DA) signaling critical for ASD pathology. DLG4 encodes PSD-95, a synapse-associated protein essential for NMDA receptor function and synaptic plasticity, while PAX5 plays a role in DA neuron development. AST-001 also regulates the expression of Synaptosome Associated Protein 23 (SNAP23), a ubiquitously expressed soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein that plays a critical role in membrane fusion processes. Small RNA sequencing identified key miRNAs - mmu-miR-378c, mmu-miR-483-5p, mmu-miR-3085-3p, and mmu-miR-128-3p - as regulators of DLG4, PAX5, and SNAP23 in ASD. These findings suggest that AST-001 may affect miRNA-gene interactions involved in ASD, providing a promising direction for miRNA-based therapeutic approaches.