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New UC Davis study reports behavioral rescue in a mouse model of Angelman syndrome

This week we are highlighting an exciting publication that came from FAST-funded research from Drs. Dave Segal, Jill Silverman and Kyle Fink at the University of California, Davis that reported behavioral rescue in an adult mouse model of Angelman syndrome following administration of a zinc-finger artificial transcription factor (ATF) targeting the long non-coding antisense transcript (Ube3a-ATS) that normally silences paternal Ube3a expression. This is an approach of “stopping the stop.”

As a quick reminder, everyone has both a mom (maternal) and dad (paternal) copy of UBE3A in the brain and the paternal copy is normally silenced due to a long piece of RNA called the antisense transcript (UBE3A-ATS). This UBE3A-AS transcript is normally designed to bind to the dad’s copy and which prevents paternal UBE3A protein production through the silencing phenomenon called “imprinting”. This is fine when the maternal copy can produce functional UBE3A, since only one copy is needed in neurons of the brain, but in the case of Angelman syndrome where the maternal UBE3A gene does not produce the UBE3A protein, a promising approach lies in turning on, or reactivating, paternal UBE3A by unsilencing the paternal copy of the gene.

A zinc-finger artificial transcription factor (ATF) is an engineered protein that binds to a specific sequence in the genome and modulates (changes) gene expression. This is designed for a specific target, and in this case it was designed for the UBE3A-ATS to “stop the stop” and activate the paternal copy of the UBE3A gene.

Creating these artificial transcription factors requires extensive purification efforts and the protein is quickly degraded (used up) in the body so, in this recently published article, they were able to package the transcription factor in an AAV viral vector for a single-dose administration. 

After a single dose of the artificial transcription factor packaged in the AAV, which was then administered to young adult mice, they were able to observe a reduction in the Ube3a-ATS and an increase in Ube3a protein expression throughout the mouse brain. The treatment was well tolerated without a significant immune response. Strikingly, the treatment improved motor abilities in mice that received it including overall activity, motor learning, balance/coordination, and gait metrics. This is an exciting new study that supports our Pillar 2 approach focusing on another paternal reactivation strategy, further aligning with the idea that treatment at later developmental time points (in this case adult-treated mice) can show significant improvements in AS-related behavioral outcomes.

To access the full paper, click on the link here:

Transcriptional reprogramming restores UBE3A brain-wide and rescues behavioral phenotypes in an Angelman syndrome mouse model