Antisense oligonucleotide treatment rescues UBE3A expression and multiple phenotypes of an Angelman syndrome mouse model

Claudia Milazzo, Edwin J. Mientjes, Ilse Wallaard, Søren Vestergaard Rasmussen, Kamille Dumong Erichsen, T (Teja) Kakunuri, Erasmus MC, Thomas Kremer, Meghan T. Miller, Marius C. Hoener, Ype Elgersma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations affecting the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene. Previous studies showed that the silenced paternal Ube3a gene can be activated by targeting the antisense Ube3a-ATS transcript. We investigated antisense oligonucleotide-induced (ASO-induced) Ube3a-ATS degradation and its ability to induce UBE3A reinstatement and rescue of AS phenotypes in an established Ube3a mouse model. We found that a single intracerebroventricular injection of ASOs at postnatal day 1 (P1) or P21 in AS mice resulted in potent and specific UBE3A reinstatement in the brain, with levels up to 74% of WT levels in the cortex and a full rescue of sensitivity to audiogenic seizures. AS mice treated with ASO at P1 also showed rescue of established AS phenotypes, such as open field and forced swim test behaviors, and significant improvement on the reversed rotarod. Hippocampal plasticity of treated AS mice was comparable to WT but not significantly different from PBS-treated AS mice. No rescue was observed for the marble burying and nest building phenotypes. Our findings highlight the promise of ASO-mediated reactivation of UBE3A as a disease-modifying treatment for AS.

Original languageEnglish
Article numbere145991
JournalJCI insight
Volume6
Issue number15
DOIs
Publication statusPublished - 9 Aug 2021

Bibliographical note

Funding Information:
YE is supported by grants from the Angelman Syndrome Foundation, grants from the Angelman Syndrome Alliance, and a NWO-ZonMw TOP grant. CM is supported by a grant from Associazione Angelman and Fondazione per la Ricerca Ospedale di Bergamo. We thank Mehrnoush Aghadavoud Jolfaei for genotyping and generating and analyzing the LTP data and Minetta Elgersma-Hooisma for mouse colony management and valuable input on the manuscript.

Funding Information:
YE is supported by grants from the Angelman Syndrome Foundation, grants from the Angelman Syndrome Alliance, and a NWO-ZonMw TOP grant. CM is supported by a grant from Associazione Angel-man and Fondazione per la Ricerca Ospedale di Bergamo. We thank Mehrnoush Aghadavoud Jolfaei for genotyping and generating and analyzing the LTP data and Minetta Elgersma-Hooisma for mouse colony management and valuable input on the manuscript.

Funding Information:
funded by F. Hoffmann-La Roche Ltd.

Publisher Copyright:
Copyright: © 2021, Milazzo et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

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