Deb Roy Submitted:

My presentation will describe a research pipeline we are building to better understand the molecular and cellular basis of Duplication 15q syndrome (Dup15q), a genetic neurodevelopmental disorder (NDD) that is often associated with autism spectrum disorder (ASD), developmental delays, intellectual disability, and refractory seizures.

My work focuses on UBE3A, a gene in the duplicated 15q11-13 chromosome region that is thought to play a pivotal role in the disorder. Using primary neurons cultured from a mouse model showing increased Ube3a dosage, we are developing an in vitro pipeline to measure how changes in gene dosage and subsequent protein expression may affect neuronal growth, maturation, and communication across neural networks. We use imaging methods to examine cell structure and high-density multielectrode arrays (HD-MEA) to monitor patterns of electrical activity as networks develop over time. This allows us to study how excess UBE3A may contribute to abnormal brain network activity relevant to Dup15q. We are also using this platform to compare multiple model systems, including primary mouse neurons and human stem cell-derived neurons, to better understand how developmental and species-specific contexts may influence disease-related phenotypes.

In parallel, we are evaluating targeted therapeutic strategies designed to lower or normalize UBE3A activity back to wildtype levels, including antisense oligonucleotides (ASOs) and Lipid nanoparticle delivered-gene-editing approaches. Overall, this work aims to create a standardized, translational platform that seeks to connect UBE3A dosage to quantifiable changes at a cellular and network level, while simultaneously assessing potential therapeutic rescue strategies.