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Treatment of Seizures Associated with Angelman Syndrome
Duke-NUS Medical School
Small molecule
Neurology
Target Identification or Validation
Unmet Needs and Current Approach
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by delayed development, intellectual disability, and frequent episodes of seizures. Currently, there is no cure available for AS and, since it can result in multiple varieties of seizures, selection of appropriate anticonvulsant medications to treat epilepsy can be difficult. Approximately 90% of AS cases are caused by the loss of function of the UBE3A gene, which encodes an HECT E3 ubiquitin ligase, and the loss of the UBE3A protein could result in the build-up of AS-relevant substrate proteins, contributing to disease pathogenesis. Previous studies that have provided a number of mechanistic insights by demonstrating impaired synaptic connectivity, an imbalance between network excitation and inhibition, and delayed neurodevelopmental processes. However, no concurrent mechanism has been fully established to underlie epilepsy, a common feature in AS patients. Likewise, although new information gathered using AS patient-derived induced pluripotent stem cells (AS-iPSCs) and differentiated neurons reveals several cellular deficits, neither the pathological mechanism underlying AS nor the biological substrate(s) of UBE3A has been characterized.
Our Solution
Associate Professor Shawn Je’s team at the Neuroscience and Behavioural Disorders department of Duke-NUS Medical School has identified a new target of UBE3A, the big conductance calcium-activated potassium (BK) channel. Using human neurons and brain organoids, a novel role for UBE3A was identified, whereby it suppresses neuronal hyperexcitability via the ubiquitin-mediated degradation of BK channels. They further demonstrated that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization, and that these effects could be normalized by BK antagonists. In short, the researchers at Duke-NUS identified a novel channelopathy as an important pathophysiological mechanism contributing to the network dysfunction and hyperactivity observed in AS.
Dr. Je’s lab has expertise in generating human cortical brain organoids from human embryonic stem cell lines and AS patient induced pluripotent stem cells (iPSCs). Along with these human cortical organoid systems, the lab also has UBE3Am-/p+ mice to study potential new BK antagonists.
Alfred Xuyang Sun, Qiang Yuan
PCT-SG2020-050762 (2020.12.18)
Patent Family: US, EP
"Potassium channel dysfunction in human neuronal models of Angelman syndrome". Sun, A. X. et al. Science 2019, 366(6472), 1486–1492
