Rodent Models and How They Define Potential Human Benefit: A Translational Review for Angelman Syndrome

• Description: UBE3A silencing in primates consolidates around birth, leaving paternal UBE3A protein robustly expressed throughout early embryonic development. This developmental timing supports a largely postnatal pathogenesis in Angelman syndrome (AS) and provides a rationale for therapeutic benefit beyond infancy. Here we review AS genetics and imprinting biology, compare human and model-organism developmental timelines, and synthesize lessons from numerous AS mouse models, while simultaneously highlighting both their value for defining molecular mechanisms, biodistribution, and pharmacology, and their limits for predicting complex human outcomes. We summarize therapeutic strategies under evaluation (gene replacement, paternal allele unsilencing via antisense oligonucleotides or genome/epigenome editing, and hematopoietic stem-cell–based approaches) and emerging human trial results. Across modalities, data support the potential for meaningful rescue when UBE3A is restored postnatally across all ages, underscoring persistent circuit plasticity and the need for inclusive, age-spanning clinical trials, including newborn to adult ages, guided by rigorous biomarkers and translational endpoints.