Longitudinal EEG model detects antisense oligonucleotide treatment effect and increased UBE3A in Angelman syndrome

• DOI: 10.1093/braincomms/fcac106
• Publication Date: 2022-04-26T03:20:03Z
• Authors: Elizabeth R. Spencer; Wen Shi; Robert W. Komorowski; James P. Gilbert; Lauren M. Ostrowski; Lynne M. Bird; Ronald Thibert; Channa Bao; Fiona Molloy; Michael Calhoun; Samir Koirala; Paymaan Jafar-nejad; Frank Rigo; Mark A. Kramer; Catherine J. Chu
• Keywords: UBE3A; Angelman Syndrome

Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A gene in neurons. Antisense oligonucleotide therapies are under development to reinstate protein production. Non-invasive biomarkers detect target engagement and treatment response needed support clinical trials. Delta power measured scalp EEG reliable biomarker for but varies widely across individuals throughout development, making detection effect using single measurements challenging. We utilized longitudinal dataset 204 recordings from 56 subjects with develop natural history model delta (2-4 Hz) power, predictors age, elapsed time, relative at an initial recording. Using this model, we computed sample sizes human trial 80% power. applied same structure mouse (n = 41) antisense oligonucleotide-mediated effects on absolute activity Ube3a expression. In humans, second time point can be reliably predicted model. mice, detected after targeting Ube3a-antisense transcript through least 8 weeks post-treatment (P < 1e-15). Deviations expected correlated expression 0.001). improvement mice may relevant