Prof. Dr. Ype Elgersma, PhD Submitted:

Our laboratory investigates the molecular and cellular mechanisms that drive neurodevelopmental disorders, with the overarching goal of translating fundamental discoveries into therapeutic strategies. Our work is organized into three complementary research lines: advancing genetic diagnostics, elucidating disease mechanisms, and conducting translational studies aimed at improving patient quality of life. This work is performed within the Erasmus MC Expertise center for Neurodevelopment (ENCORE) which includes an Angelman syndrome (AS) and Dup15q clinic. Both disorders are driven by changes in UBE3A levels. UBE3A encodes a ubiquitin ligase essential for protein turnover, and over the past decades we learned a lot about UBE3A biology. Nevertheless, its precise neuronal function and the pathways disrupted by its absence remain an important aspect of investigation. To address this gap, we employ both animal models and in vitro systems to dissect UBE3A-dependent processes. Despite the rather limited mechanistic insight, therapeutic progress has accelerated through the development of antisense oligonucleotides (ASOs) that unsilence the normally imprinted paternal UBE3A allele. Several ASOs have now entered clinical trials, underscoring the urgency of answering key outstanding questions: the level of UBE3A required for functional rescue, the brain regions most critical for therapeutic targeting, and whether UBE3A reinstatement alone is sufficient in individuals with large chromosomal deletions affecting multiple genes. We are actively addressing these questions using established AS mouse models and newly generated lines, such as an AS mouse model for Type I deletion to refine therapeutic strategies and deepen mechanistic understanding.