Autism spectrum disorder (ASD) represents a group of hundreds of individually rare conditions which are in large measure due to mutations in genes produced in the brain. While the molecular characterization of ASD has advanced in recent years and many individuals with ASD now receive a molecular diagnosis, there are few if any treatments that are specific to the molecular cause.

Joseph Gleeson and colleagues previously identified the first treatable cause of ASD, due to mutations in the branched chain ketoacid decarboxylase kinase gene, which can be metabolically corrected through dietary supplementation¹. But approaching the larger group of people with ASD will require a different strategy, as most genes do not offer a straightforward way to correct the pathology.

In the current project, Gleeson proposes to generate cell-based preclinical models to assess potential effectiveness of antisense oligonucleotides (ASOs) to treat certain genetic forms of ASD. Their rationale is that severe ASD is often due to de novo mutations in brain-expressed genes and that many of these mutations lead to gene hyperactivation. Gleeson’s team has profiled all known human mutations and determined which could be approached therapeutically with an ASO². By modulating the expression of these genes, they will test the degree to which ASOs that specifically target particular ASD mutations can show correction of the underlying transcriptional alteration and cell biological changes. These experiments will be performed both in neurons derived from induced pluripotent stem cells (iPSCs) from affected individuals as well as neurons derived from control iPSCs in which the patient mutation has been introduced.

This work is coordinated with the non-profit n-Lorem Foundation — which has agreed to generate ASOs as drugs and provide them to patients for free — as well as with latter and treating physicians. If the ASOs that the Gleeson lab develops can be proven safe and effective, they will be proposed to the Food and Drug Administration (FDA) as new medications to treat certain forms of ASD. The work proposed in this application is thus limited to preclinical assessment, but it has the potential to translate into novel therapeutics for ASD.