Autism spectrum disorder (ASD) has a complex genetic landscape with many highly penetrant risk genes which individually affect a small proportion of individuals with a spectrum of clinical manifestations. Therapeutic interventions are currently lacking, and strategies that precisely target specific disease-causing mechanisms to modify ASD onset and progression will be critical to address the tremendous gap in unmet medical needs.

Recent genetic studies demonstrated that de novo loss-of-function mutations disproportionally affect a group of genes encoding chromatin regulators, resulting in their haploinsufficiency. Conceptually, upregulation of the functional protein by two-fold in relevant tissues and cell types should lead to therapeutic benefits for these ASD cases.

Chaolin Zhang and his colleagues aim to target alternative splicing, a ubiquitous and highly regulated molecular mechanism that produces multiple transcript variants, to develop potential therapeutics for ASD and other neurodevelopmental conditions. While alternative splicing can produce multiple protein-coding isoforms, it also frequently generates a combination of protein-coding and noncoding isoforms, with the noncoding isoform degraded by the nonsense-mediated decay (NMD) pathway.

Previous work from the Zhang lab found that conserved NMD exons are particularly enriched in genes encoding chromatin regulators¹, suggesting their importance for regulating the homeostatic levels of these proteins. Building on this observation, the team aims to restore functional protein production by using an antisense oligonucleotide (ASO) to suppress the NMD isoform and upregulate the protein-coding isoform from the intact allele.

Zhang’s team will perform systematic ASO screening in human cell lines (e.g., HEK) to identify the most effective ASOs as drug leads. They will then validate their efficacy in correcting molecular and cellular deficits caused by haploinsufficiency using forebrain organoids derived from induced pluripotent stem cells that carry the loss-of-function mutations. If successful, this study will provide a critical first step towards the development of ASO therapeutics for ASD and related neurodevelopmental conditions caused by dominant haploinsufficiencies.