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 GNAO1, as a spectrum of neurological phenotypes, including epileptic encephalopathy, developmental delay with movement disorders, or late-onset dystonia. There ar...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124003196 |
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| author | Inna Shomer Nofar Mor Shaul Raviv Noga Budick-Harmelin Tanya Matchevich Sharon Avkin-Nachum Yoach Rais Rebecca Haffner-Krausz Ariela Haimovich Aviv Ziv Reut Fluss Bruria Ben-Ze’ev Gali Heimer Denis N. Silachev Vladimir L. Katanaev Dan Dominissini |
| author_facet | Inna Shomer Nofar Mor Shaul Raviv Noga Budick-Harmelin Tanya Matchevich Sharon Avkin-Nachum Yoach Rais Rebecca Haffner-Krausz Ariela Haimovich Aviv Ziv Reut Fluss Bruria Ben-Ze’ev Gali Heimer Denis N. Silachev Vladimir L. Katanaev Dan Dominissini |
| author_sort | Inna Shomer |
| collection | DOAJ |
| description | GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in GNAO1, 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 GNAO1 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 GNAO1 in vitro 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 in vitro using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated GNAO1 by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach. |
| format | Article |
| id | doaj-art-d79b5d60474b446aa200fe6a1350f381 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-d79b5d60474b446aa200fe6a1350f3812025-01-18T05:04:24ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102432Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorderInna Shomer0Nofar Mor1Shaul Raviv2Noga Budick-Harmelin3Tanya Matchevich4Sharon Avkin-Nachum5Yoach Rais6Rebecca Haffner-Krausz7Ariela Haimovich8Aviv Ziv9Reut Fluss10Bruria Ben-Ze’ev11Gali Heimer12Denis N. Silachev13Vladimir L. Katanaev14Dan Dominissini15Cancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, Israel; Corresponding author: Nofar Mor, Cancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, Israel.Cancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelDepartment of Veterinary Resources, Weizmann Institute of Science, Rehovot, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, IsraelSheba Medical Center, Edmond and Lilly Safra Children’s Hospital, Tel Hashomer, IsraelSheba Medical Center, Edmond and Lilly Safra Children’s Hospital, Tel Hashomer, IsraelInstitute of Life Sciences and Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; A.N. Belozersky Research Institute of Physico-Chemical Biology, Moscow State University, 119992 Moscow, Russia; Department of Cell Physiology and Metabolism, Faculty of Medicine, Translational Research Center in Oncohaematology, University of Geneva, 1211 Geneva, SwitzerlandInstitute of Life Sciences and Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia; Department of Cell Physiology and Metabolism, Faculty of Medicine, Translational Research Center in Oncohaematology, University of Geneva, 1211 Geneva, SwitzerlandCancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Corresponding author: Dan Dominissini, Cancer Research Center and Wohl Institute for Translational Medicine, Tel Hashomer, Ramat Gan, Israel.GNAO1-associated disorders are ultra-rare autosomal dominant conditions, which can manifest, depending on the exact pathogenic variant in GNAO1, 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 GNAO1 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 GNAO1 in vitro 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 in vitro using murine neural progenitor cells. Our results demonstrate a beneficial effect for the reduction of mutated GNAO1 by ASO in patient-derived models, demonstrating its feasibility as a therapeutic approach.http://www.sciencedirect.com/science/article/pii/S2162253124003196MT: Oligonucleotides: Therapies and ApplicationsGNAO1personalized ASOsantisense oligonucleotidesASOsindividualized ASOs |
| spellingShingle | Inna Shomer Nofar Mor Shaul Raviv Noga Budick-Harmelin Tanya Matchevich Sharon Avkin-Nachum Yoach Rais Rebecca Haffner-Krausz Ariela Haimovich Aviv Ziv Reut Fluss Bruria Ben-Ze’ev Gali Heimer Denis N. Silachev Vladimir L. Katanaev Dan Dominissini Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications GNAO1 personalized ASOs antisense oligonucleotides ASOs individualized ASOs |
| title | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder |
| title_full | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder |
| title_fullStr | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder |
| title_full_unstemmed | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder |
| title_short | Personalized allele-specific antisense oligonucleotides for GNAO1-neurodevelopmental disorder |
| title_sort | personalized allele specific antisense oligonucleotides for gnao1 neurodevelopmental disorder |
| topic | MT: Oligonucleotides: Therapies and Applications GNAO1 personalized ASOs antisense oligonucleotides ASOs individualized ASOs |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124003196 |
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