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In vivo repair of a protein underlying a neurological disorder by programmable RNA editing

John R Sinnamon, Susan Y Kim, Jenna R Fisk, Zhen Song, Hiroyuki Nakai, Sophia Jeng, Shannon K McWeeney, Gail Mandel
doi: https://doi.org/10.1101/2020.02.26.966820
John R Sinnamon
1Vollum Institute, Oregon Health and Science University, Portland, OR, USA, 97239
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  • For correspondence: sinnamon@ohsu.edu mandelg@ohsu.edu
Susan Y Kim
1Vollum Institute, Oregon Health and Science University, Portland, OR, USA, 97239
2Universal Cells, Inc., Seattle, WA, USA, 98121
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Jenna R Fisk
1Vollum Institute, Oregon Health and Science University, Portland, OR, USA, 97239
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Zhen Song
3Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA
2Universal Cells, Inc., Seattle, WA, USA, 98121
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Hiroyuki Nakai
3Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA
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Sophia Jeng
4Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA, 97239
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Shannon K McWeeney
4Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA, 97239
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Gail Mandel
1Vollum Institute, Oregon Health and Science University, Portland, OR, USA, 97239
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  • For correspondence: sinnamon@ohsu.edu mandelg@ohsu.edu
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Abstract

RNA base editing is gaining momentum as an approach to repair mutations, but its application to neurological disease has not been established. We have succeeded in directed transcript editing of a pathological mutation in a mouse model of the neurodevelopmental disease, Rett syndrome. Specifically, we directed editing of a guanosine to adenosine mutation in RNA encoding Methyl CpG Binding Protein 2 (MECP2). Repair was mediated by injecting the hippocampus of juvenile Rett mice with an adeno-associated virus expressing both an engineered enzyme containing the catalytic domain of Adenosine Deaminase Acting on RNA 2 and a Mecp2 targeting guide. After one month, 50% of Mecp2 RNA was recoded in three different hippocampal neuronal subtypes, and the ability of MeCP2 protein to associate with heterochromatin was similarly restored to 50% of wild-type levels. This study represents the first in vivo programmable RNA editing applied to a model of neurological disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 27, 2020.
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In vivo repair of a protein underlying a neurological disorder by programmable RNA editing
John R Sinnamon, Susan Y Kim, Jenna R Fisk, Zhen Song, Hiroyuki Nakai, Sophia Jeng, Shannon K McWeeney, Gail Mandel
bioRxiv 2020.02.26.966820; doi: https://doi.org/10.1101/2020.02.26.966820
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In vivo repair of a protein underlying a neurological disorder by programmable RNA editing
John R Sinnamon, Susan Y Kim, Jenna R Fisk, Zhen Song, Hiroyuki Nakai, Sophia Jeng, Shannon K McWeeney, Gail Mandel
bioRxiv 2020.02.26.966820; doi: https://doi.org/10.1101/2020.02.26.966820

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