Emerging disease-modifying therapies for Angelman syndrome: A comprehensive review for pediatric neurologists

Angelman syndrome (AS), a rare neurogenetic disorder affecting approximately 1 in 15,000 live births, results from loss of functional UBE3A gene expression and manifests with severe developmental delay, intellectual disability, absent speech, ataxia, epilepsy, and distinctive behavioral features. Until recently, only symptomatic management was available. This review provides pediatric neurologists with a comprehensive, practice-oriented overview of emerging disease-modifying therapies for AS, focusing on therapeutic approaches advancing through clinical development. The molecular pathophysiology of AS, natural history considerations critical for trial interpretation, and the current evidence for antisense oligonucleotide (ASO) therapies (ION582, GTX-102/apazunersen, rugonersen), gene replacement approaches (MVX-220), and next-generation strategies including CRISPR-based gene editing, artificial transcription factors, small molecules, and novel delivery platforms are reviewed. ASO therapies targeting the UBE3A antisense transcript represent the most clinically advanced approach, with three candidates showing proof-of-concept efficacy in Phase 1/2 studies and two advancing to pivotal Phase 3 trials. Gene replacement therapy offers potential single-administration treatment but faces challenges regarding safety, immune responses, and durability. Next-generation approaches including CRISPR activation, epigenetic editing, and blood-brain barrier-penetrating delivery systems show preclinical promise. Critical challenges include outcome measurement limitations, genotype stratification, long-term safety monitoring, and ensuring equitable access. These advances herald a transformation in AS clinical care and represent a milestone in precision pediatric neurology.