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

Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms and Sleep in Juvenile and Adult Mouse Models of Angelman Syndrome Lee D, Chen W, Kaku HN, Zhuo X, Chao ES, Soriano A, Kuncheria A, Flores S, Kim JH, Rivera A, Rigo F, Jafar-Nejad P, Beaudet AL, Caudill MS, Xue M. Elife. 20233;12:e81892. doi:10.7554/eLife.81892 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 (EEG) 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 EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies. [ABSTRACT FROM AUTHOR]