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UBE3A enzyme replacement therapy rescues symptoms of Angelman syndrome in the rat model

Recently a collaborative team from the University of South Florida (USF), Tampa, led by principal investigator Dr. Kevin Nash, and the University of California at Davis, led by Drs. David Segal and Jill Silverman, generated and described a new Angelman syndrome (AS) rat model with the complete gene deletion of Ube3a. Animal models provide opportunities for scientists to better understand how a drug can improve the symptoms of AS. Numerous mouse models exist for AS, but compared to the rat model, they are small, have very rudimentary behaviors, and have less translatable symptoms to humans living with AS. The AS rat model is a promising way to investigate potential AS treatments and has complemented the existing AS mouse models.

Using the AS rat model, the research team at USF identified the presence of the Ube3a enzyme outside of the cells in the brain. This enzyme is found in most body cells, but its lack of function in neurons is the leading cause of symptoms of AS. By finding the presence of this protein outside of neurons of the brain, it led to the hypothesis that there is a function of the protein outside of these cells, opening up the consideration of the potential benefit of this protein to be both inside and outside of neurons to reach maximal benefit of symptom improvement. 

One part of the brain, the hippocampus, is a complex brain structure that plays a significant role in learning, emotional response, and memory formation – all important aspects for AS. The research team hypothesized that this UBE3A protein, if injected into the hippocampus outside of the neurons, could allow for improvement in the symptoms of learning and memory. Indeed, this was the case and these symptoms improved.

The UBE3A enzyme was introduced into the rat brain, bathing the outside of the cells of the hippocampus, and this resulted in recovery in learning and memory deficits – an important finding in AS research. This further supports future therapeutic considerations that FAST has been actively funding, including enzyme replacement therapy (ERT), hematopoietic progenitor cell gene therapy (HSC-GT) by cross-correction and AAV-STUB (cross correction-secreted UBE3A). These approaches take advantage of the concept that the protein being outside of the cell can have an important role.

What does this research data mean for a C.U.R.E-ASTM? Overall, the data from this project supports that the UBE3A protein, when present outside of the cells, may have a functional role in how effectively the neurons communicate with one another (synaptic transmission). This is another step closer to understanding the best location for UBE3A to be delivered in a gene or protein replacement therapy. This study adds to the growing knowledge base of the complexity of UBE3A, suggesting that UBE3A may have different functions in different parts of the cell within and outside of neurons. Understanding if there is a need for extracellular UBE3A allows for further exploration and pursuit of some of the most promising therapies FAST is funding to date.