AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Aoife Campbell; Gareth Morris; Albert Sanfeliu; Joana Augusto; Elena Langa; Jaideep C Kesavan; Ngoc T Nguyen; Ronan M Conroy; Jesper Worm; Lukasz Kielpinski; Mads Aaboe Jensen; Meghan T Miller; Thomas Kremer; Cristina R Reschke; David C Henshall

doi:10.1016/j.omtn.2022.04.009

AntimiR targeting of microRNA-134 reduces seizures in a mouse model of Angelman syndrome

Mol Ther Nucleic Acids. 2022 Apr 20:28:514-529. doi: 10.1016/j.omtn.2022.04.009. eCollection 2022 Jun 14.

Authors

Aoife Campbell^{1

2}, Gareth Morris^{1

2}, Albert Sanfeliu^{1

2}, Joana Augusto^{1

2}, Elena Langa^{1

2}, Jaideep C Kesavan^{1

2}, Ngoc T Nguyen^{1

2}, Ronan M Conroy³, Jesper Worm⁴, Lukasz Kielpinski⁴, Mads Aaboe Jensen⁴, Meghan T Miller⁵, Thomas Kremer⁵, Cristina R Reschke^{1

2

6}, David C Henshall^{1

2}

Affiliations

¹ Department of Physiology and Medical Physics, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
² FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
³ Department of Public Health and Epidemiology, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
⁴ Therapeutic Modalities, Roche Innovation Center Copenhagen A/S, F. Hoffmann-La Roche Ltd, DK-2970 Hørsholm, Denmark.
⁵ Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland.
⁶ School of Pharmacy and Biomedical Sciences, RCSI University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder featuring ataxia, cognitive impairment, and drug-resistant epilepsy. AS is caused by mutations or deletion of the maternal copy of the paternally imprinted UBE3A gene, with current precision therapy approaches focusing on re-expression of UBE3A. Certain phenotypes, however, are difficult to rescue beyond early development. Notably, a cluster of microRNA binding sites was reported in the untranslated Ube3a1 transcript, including for miR-134, suggesting that AS may be associated with microRNA dysregulation. Here, we report levels of miR-134 and key targets are normal in the hippocampus of mice carrying a maternal deletion of Ube3a (Ube3a ^m-/p+ ). Nevertheless, intracerebroventricular injection of an antimiR oligonucleotide inhibitor of miR-134 (Ant-134) reduced audiogenic seizure severity over multiple trials in 21- and 42-day-old AS mice. Interestingly, Ant-134 also improved distance traveled and center crossings of AS mice in the open-field test. Finally, we show that silencing miR-134 can upregulate targets of miR-134 in neurons differentiated from Angelman patient-derived induced pluripotent stem cells. These findings indicate that silencing miR-134 and possibly other microRNAs could be useful to treat clinically relevant phenotypes with a later developmental window in AS.

Keywords: Angelman syndrome; Behavior; Cerebellum; Hippocampus; MT: Oligonucleotides: Therapies and Applications; epilepsy; miR-134; microRNAs; seizures.