Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.

GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in , as a spectrum of neurological phenotypes, including epileptic encephalopathy, developmental delay with movement disorders, or late-onset dystonia. There are currently no effective treatments available, apart from symptomatic options. In this work, we suggest harnessing personalized RNA therapy to treat patients and focus specifically on a recurrent pathogenic variant (E246K). We systemically screened allele-specific antisense oligonucleotides (ASOs) targeting the mutated allele to identify a potent and specific sequence using both reporter-based platforms and a patient-derived cellular model. We show that reduction of mutated by knockout or by ASO has a beneficial functional outcome, which can be measured by cAMP accumulation and gene expression changes. We established a Gnao1-E246K mouse model that shows a neurological phenotype, which partially recapitulates the human condition. Due to sequence similarity, the mouse can be treated with the selected ASO to test treatment efficacy in animal models, as shown using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach.