Large-scale genetic studies have identified hundreds of genes associated with autism spectrum disorder (ASD). Many individuals with ASD carry mutations in these genes, highlighting their potential as therapeutic targets. However, the diversity of implicated genes and the lack of evidence for a unified therapeutic pathway pose challenges to developing gene-specific treatments. This project introduces a novel platform approach to address this challenge by targeting mRNA secondary structures with small molecules to modulate protein expression in multiple high-risk ASD genes. Joseph Buxbaum and team focus on autosomal dominant genes with haploinsufficiency, where enhanced expression of the intact allele could restore wild-type protein levels. Their preliminary work demonstrates successful modulation of several genes, including increased expression of native protein for the ADNP gene. With this project, they aim to identify and validate small molecules capable of upregulating three to five ASD genes.

The project is organized into three key aims:

Target Selection: Over 100 high-confidence ASD genes will be analyzed for conserved mRNA structures. Modeling and evolutionary conservation analyses will refine this list to 10 to 20 genes for experimental targeting.

Hit Identification: A defined compound library and the InfoRNA in silico system, will be for molecules that enhance the expression of selected genes. Luciferase reporter assays will confirm hits, followed by specificity and dose-response testing.

Hit-to-Lead (H2L): Promising hits will undergo SAR analysis, validation with endogenous proteins in human neurons, and target engagement studies. The goal is to identify three to five lead compounds suitable for preclinical development.