biostudies-literatureShomer IRussian Science Foundation102432https://www.ebi.ac.uk/biostudies/studies/S-EPMC11787015biostudies-literatureUnknown36(1)GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in <i>GNAO1</i>, 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 <i>GNAO1</i> 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 <Molecular therapy. Nucleic acidsPersonalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder.PMC1178701521-15-00138Avkin-Nachum SBen-Ze'ev BRais YFluss RShomer IHaffner-Krausz RZiv AKatanaev VLMor NRaviv SHeimer GSilachev DNHaimovich ABudick-Harmelin NMatchevich TDominissini DfalsePersonalized 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 <i>GNAO1</i>, 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 <i>GNAO1</i> 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 <2025-01-01T00:00:00Z2025 Mar2026-06-01T10:26:10.579Z2025-04-03T23:36:31.612ZS-EPMC117870153989757610.1016/j.omtn.2024.102432