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Concise CommunicationIn-Press PreviewGeneticsNeuroscience Free access | 10.1172/JCI142574

CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice

Ralf S. Schmid,1 Xuefeng Deng,1 Priyalakshmi Panikker,1 Msema Msackyi,1 Camilo Breton,1 and James M. Wilson1

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Schmid, R. in: JCI | PubMed | Google Scholar |

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Deng, X. in: JCI | PubMed | Google Scholar

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Panikker, P. in: JCI | PubMed | Google Scholar |

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Msackyi, M. in: JCI | PubMed | Google Scholar

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Breton, C. in: JCI | PubMed | Google Scholar

1Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States of America

Find articles by Wilson, J. in: JCI | PubMed | Google Scholar

Published January 7, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI142574.
Copyright © 2021, American Society for Clinical Investigation
Published January 7, 2021 - Version history
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Abstract

Gene editing holds the potential to correct mutations and cure devastating genetic disorders. The technology has not yet proven efficacious for therapeutic use in central nervous system (CNS) diseases with ubiquitous neuronal defects. Angelman syndrome (AS), a severe neurodevelopmental disorder, is caused by a lack of maternal expression of the UBE3A gene. Due to genomic imprinting, only neurons are affected. One therapeutic approach focuses on the intact paternal UBE3A copy in AS patients that is silenced by an antisense transcript (UBE3A-ATS). We show here that gene editing of Ube3a-ATS in the mouse brain results in the formation of base pair insertions/deletions (indels) in neurons and the subsequent unsilencing of the paternal Ube3a allele in neurons, which partially corrects the behavior phenotype of a murine AS model. This study provides compelling evidence to further investigate editing of the homologous region of the human UBE3A-ATS, since this may provide a lasting therapeutic effect for AS patients.

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