Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

Abstract

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and electroencephalogram power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.

Adult Gene Therapy for Epilepsy in a Model of Angelman Syndrome: Hope or Hype?

“…Early preclinical UBE3A gene therapy trials in mice showed efficacy, but only with very early treatment, before the second day of life (reviewed in supplemental files of study by Lee et al 9 ). Here Lee and colleagues 9 used a novel gene therapy approach and show partial restoration of function with antisense oligonucleotide gene knockdown approaches in juvenile , and to a lesser extent in adult mice engineered with maternal UBE3A deficiency.…”

“…Early preclinical UBE3A gene therapy trials in mice showed efficacy, but only with very early treatment, before the second day of life (reviewed in supplemental files of study by Lee et al 9 ). Here Lee and colleagues 9 used a novel gene therapy approach and show partial restoration of function with antisense oligonucleotide gene knockdown approaches in juvenile , and to a lesser extent in adult mice engineered with maternal UBE3A deficiency. As the paternal copy of UBE3A is repressed by a specific endogenous antisense sequence (UBE3A-ATS), genetic restoration of the paternal copy through exogenous antisense oligonucleotides (ASOs) targeting UBE3A-ATS is possible; this approach was adopted by Lee and colleagues.…”

“…Severe seizures, a very common issue for human AS patients, are not observed in UBE3A mutant mice. 9 Instead, only mild EEG abnormalities are reported (polyspikes and altered seizure susceptibility). Similarly, cognitive deficits are not a reliable feature in UBE3A mutant mice (see authors’ response to reviewers, 9 always available for eLife papers).…”

“… 9 Instead, only mild EEG abnormalities are reported (polyspikes and altered seizure susceptibility). Similarly, cognitive deficits are not a reliable feature in UBE3A mutant mice (see authors’ response to reviewers, 9 always available for eLife papers). A related second major concern is that gene therapies tested in such monogenetic models may have limited ability to predict the expected improvement in the vast majority of patients: those with altered gene function beyond UBE3A deficiency.…”

How late is too late for treatment?

“…However, there are not many studies that dig deeper into the cognitive issues, sleep or epilepsy-related brain activity (as measured with EEG) that are known to be affected in this mouse model. Now, in eLife, Mingshan Xue and colleagues from Baylor College of Medicine and Ionis Pharmaceuticals – including Dongwon Lee, Wu Chen, Heet Naresh Kaku and Xinming Zhuo as first authors – report on the use of an ASO to rescue the characteristic EEG pattern and disordered sleep observed in a mouse model of Angelman syndrome ( Lee et al, 2023 ).…”