Methods of Treating Angelman Syndrome and Related Disorders
PATENT STATUS
U.S. provisional patent application filed in December 2019.
OVERVIEW OF TECHNOLOGY ON OFFER
A new therapeutic strategy that involves targeting the big conductance calcium-activated potassium (BK) channel expression and/or activity to treat Angelman syndrome (AS) and other related diseases.
BRIEF DESCRIPTION
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. It has been postulated that the loss of the UBE3A protein could result in the build-up of AS-relevant substrate proteins and thereby contribute to disease pathogenesis. Previous studies that have used multiple lines of AS model mice 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.
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. This work suggests that BK channels act as a putative substrate for UBE3A, implying that targeting BK is a potential therapeutic approach to treat patients with AS.
POTENTIAL APPLICATIONS
Treatment of Angelman Syndrome and other neurological disorders characterized by seizures.
KEY BENEFIT
Targeting a specific molecular candidate (BK channels) for treatment of Angelman Syndrome and other neurological disorders characterized by seizures.
PUBLICATION
Sun, Alfred Xuyang, et al. "Potassium channel dysfunction in human neuronal models of Angelman syndrome." Science 366.6472 (2019): 1486-1492.
PRESS COVERAGE
Scientists in Singapore discover mechanism causing epilepsy in Angelman syndrome (click on this text see video).
INVENTOR BIO
Hyunsoo Shawn Je
CONTACT
Please email us for further enquiries:
cted@duke-nus.edu.sg