Antisense oligonucleotides (ASOs) demonstrate promise as therapeutic approaches for treating genetic disorders of the central nervous system, as exemplified by the clinical success of nusinersen (a splice-modulating ASO for spinal muscular atrophy that corrects mis-splicing of the SMN2 gene) as well as promising ongoing ASO trials for Dravet syndrome, amyotrophic lateral sclerosis, Angelman syndrome and other related conditions.

Timothy Yu’s lab has demonstrated that ASOs can even be deployed therapeutically for orphan indications involving a single patient, having obtained Food and Drug Administration approvals to treat patients with gene- and/or mutation-specific ASOs for severely debilitating/life-threatening conditions like Batten disease, ataxia telangiectasia and KCNT1-associated developmental epileptic encephalopathy ^{^1,2}. These experiences begin to lay a foundation for developing therapeutic interventions for genetic causes of autism spectrum disorder (ASD) as well.

In this project, Yu and colleagues aim to conduct a series of experiments designed to delineate the scope of this promise for well-defined monogenic forms of ASD. They plan to focus on therapeutic applications of splice-modulating ASOs, which are simple to design, have reduced potential for off-target binding, and can be developed very quickly. Aim 1 is to apply experimental and bioinformatic techniques to generate catalogs of ASD genes and ASD mutations amenable to therapeutic intervention with splice modulating ASOs. Aim 2 is to use splice modulating ASOs to correct mRNA processing inefficiencies (and boost functional gene expression) to rescue monogenic forms of ASD caused by genetic haploinsufficiency. These would represent investigational ASO therapies that are gene-specific but mutation-agnostic. Aim 3 is to use splice modulating ASOs to correct mis-splicing caused by specific pathogenic variants associated with ASD — i.e., investigational therapies that are mutation-specific — for potential use in N-of-1 or N-of-small trials.

1. Kim J. et al. N. Engl. J. Med. 381, 1644–1652 (2019) PubMed
2. Aartsma-Rus A. et al. Nucleic Acid Ther. 33, 17–25 (2023) PubMed