FAST is thrilled to announce a new grant collaboration with Dr. Alvin Huang at Brown University, aimed at addressing oligodendroglial dysfunction prevalent in Angelman syndrome by targeting estrogen receptor signaling in both in vitro (cell) and in vivo (animal) models. This is a 1-year grant for $150,000 USD.
In the brain, the processes of learning and memory retention rely on electrical signals transmitted through vast networks of neurons. Glial cells, particularly oligodendrocytes, play a pivotal role in this information processing by providing structural support to neurons, thereby enhancing the speed of signal transmission. However, in Angelman syndrome, oligodendrocyte function is compromised, potentially impeding brain development, hindering neuronal communication, and exacerbating seizures. The underlying reasons for the dysfunction stemming from the loss of functional UBE3A remain unclear, posing challenges for targeted treatment development. Conventional gene therapies and ASOs target neurons, neglecting oligodendrocyte progenitor cells (OPCs) and glial cells, suggesting the need for a treatment candidate designed to address the UBE3A haploinsufficiency and the downstream effect of oligodendroglial dysfunction in cells other than neurons of the brain.
Preliminary findings from Dr. Xin Yang’s FAST Fellowship, conducted in collaboration with mentor Dr. Alvin Huang, have identified a class of estrogen receptor agonists (ER)capable of rescuing defective OPC proliferation and myelinating differentiation that is likely resulting from reduced UBE3A expression in those cells. This project aims to build off of these initial findings and understand how the unique biology and genetics of AS impact oligodendrocyte function. Specifically, they plan to investigate ER expression and signaling in AS patient-derived induced oligodendrocyte progenitor cells. Subsequently, they aim to evaluate the potential rescue effects of ER agonists on these cells and the AS mouse model to assess therapeutic efficacy.
The proposed research represents a novel targeted approach to address downstream oligodendroglial dysfunction, offering a promising prospect for the development of much-needed novel treatments for Angelman syndrome.