articles and announcements

Research at UNC Making Progress

November 17, 2014

Research at UNC Making Progress

PNAS Paper shows ASF-funded Research at UNC Making Progress

The ASF continues to lead the charge in funding research that is making progress towards treatments and ultimately a cure for Angelman syndrome, having invested more than $8 million during the past decade in promising AS research.

A paper published today in the Proceedings of the National Academy of Sciences by Dr. Ben Philpot, Dr. Mark Zylka and Dr. Angela Mabb at the University of North Carolina at Chapel Hill uncovered additional findings about the Angelman syndrome gene, UBE3A.


Neurotypical individuals have two copies of the Angelman syndrome gene (UBE3A), one copy inherited from their mother (the maternal copy) and one from their father (the paternal copy).  Only the maternal copy of UBE3A is “active” in neurons, thus mutation or deletion of this copy is sufficient to cause Angelman syndrome. The primary goal of the 2008 ASF Research Roadmap was to aggressively explore activation of the silenced or “inactive” paternal copy of UBE3A as a potential treatment for Angelman syndrome.


Recent studies by Dr. Ben Philpot, Dr. Mark Zylka, and Dr. Angela Mabb and their colleagues at the University of North Carolina at Chapel Hill demonstrated that Topotecan, a natural product derivative typically used to treat cancer, can unsilence the paternal copy of UBE3A. Topotecan thus represents a potential treatment for Angelman syndrome.  However, it is essential to understand the potential side effects and the impacts of using Topotecan on brain function before moving into clinical trials.  Accordingly, the studies described in this article from the Proceedings of the National Academy of Sciences continue the research group’s previous research in an effort to determine the consequences of using Topotecan or similar inhibitors in the brain.

The team took a step back from the mouse model and used an in vitro model, or neurons in a petri dish, because this provides a system to reliably and consistently deliver Topotecan to neurons.

This article illustrated that when neurons were treated with Topotecan, the goal of unsilencing the paternal copy of UBE3A was accomplished. However, during treatment, the neurons experienced a complete shutdown of activity—UBE3A was activated, but the specific cells that were treated stopped communicating with each other. However, normal neuronal activity was quickly restored once Topotecan was removed.  This result is exciting because it suggests that most treatment side effects are likely to be fully reversible.

A goal of the research is to find a treatment strategy that can provide long-term UBE3A unsilencing, as was observed with their previous research, such that the side effects of Topotecan can be completely recovered in the short-term, as was observed in the current study.

The next step to this research is to identify novel and more efficient delivery methods using Topotecan or other inhibitors like Topotecan in an AS animal model to unsilence UBE3A, to evaluate potential side effects of these treatments, and to see if Angelman syndrome symptoms in the mouse model can be reversed following drug treatment.
Click here to access the PNAS paper.