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Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder
Inna Shomer1, Nofar Mor1, Shaul Raviv1
1Cancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, Israel.
Molecular Therapy. Nucleic Acids
|February 3, 2025
Summary
Personalized RNA therapy shows promise for GNAO1-associated disorders. Antisense oligonucleotides (ASOs) effectively reduced the mutated GNAO1 gene in patient models, demonstrating a potential new treatment approach for these ultra-rare neurological conditions.
Area of Science:
- Genetics
- Neuroscience
- RNA Therapeutics
Background:
- GNAO1-associated disorders are ultra-rare autosomal dominant conditions with diverse neurological phenotypes.
- Current treatment options are limited to symptomatic management.
- A specific recurrent pathogenic variant, E246K, is a focus for therapeutic development.
Purpose of the Study:
- To explore personalized RNA therapy, specifically antisense oligonucleotides (ASOs), for treating GNAO1-associated disorders.
- To identify a potent and specific ASO sequence targeting the mutated GNAO1 allele (E246K).
- To evaluate the therapeutic efficacy of ASO treatment in patient-derived models and a Gnao1-E246K mouse model.
Main Methods:
- Systematic screening of allele-specific ASOs targeting the mutated GNAO1 allele.
- Utilized reporter-based platforms and a patient-derived cellular model for ASO screening.
- Established a Gnao1-E246K mouse model to assess in vivo efficacy.
- Validated ASO efficacy in murine neural progenitor cells.
Main Results:
- Identified potent and specific ASO sequences targeting the mutated GNAO1 allele.
- Demonstrated that reducing mutated GNAO1 in vitro via knockout or ASO treatment yields beneficial functional outcomes (cAMP accumulation, gene expression changes).
- The Gnao1-E246K mouse model partially recapitulates human neurological phenotypes.
- ASO treatment showed a beneficial effect in patient-derived models and in vitro using murine cells.
Conclusions:
- Reduction of mutated GNAO1 by ASOs is a feasible therapeutic strategy for GNAO1-associated disorders.
- Personalized RNA therapy holds promise for treating ultra-rare genetic neurological conditions.
- Further investigation in animal models supports the potential of ASO-based therapies.
