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New Angelman syndrome therapy publication from Texas A&M

An exciting publication in Science Translational Medicine titled “An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript” has just been released discussing the extensive research behind one of the first investigational molecular therapies intended for Angelman syndrome that is currently in clinical trials (, NCT04259281). 

What prevents paternal UBE3A expression in the brain? The paternal copy is normally silenced due to a long piece of RNA called the antisense transcript (UBE3A-AS). This UBE3A-AS transcript prevents the father’s copy of UBE3A from being expressed through the silencing phenomenon called “imprinting”. This means there is very little or no UBE3A protein being made in the brain of individuals living with Angelman syndrome. Antisense oligonucleotides (ASOs) are small pieces of engineered DNA and RNA that can bind to a designated target, such as the UBE3A-AS, to “knock it down” (or inhibit its expression), and allow the paternal UBE3A protein to be produced, which we also refer to as “stopping the stop.” This is part of FAST’s Pillar 2 approach in the Roadmap to a Cure for Angelman syndrome.

In this new paper, Dr. Scott Dindot and his team shared how they sought to optimize an investigational ASO candidate for Angelman syndrome. First, they looked at the make-up of the human UBE3A-AS compared to the UBE3A-AS in different animal species, understanding the importance of the evolution of this particularly unique region over time. Next, they investigated a region to target with ASOs that was both highly specific, able to inhibit the human UBE3A-AS, and activate the father’s copy of the UBE3A gene. 

A portion of the UBE3A-AS transcript was found to be genetically unique and identical to the sequence in monkeys (non-human primates), allowing for many human-specific ASOs to be developed and be assessed in this model. They designed human-specific ASOs for the target region and first screened them in a human-induced stem cell line to test for changes in the UBE3A-AS transcript levels. All these ASOs significantly reduced the UBE3A-AS transcript levels in human cell lines and showed an increase in the expression of the father's copy of the human UBE3A gene

The lead ASO candidates were then administered to monkeys  (specifically cynomolgus macaques) via a spinal tap, similar to what is being done in clinical trials. The UBE3A-AS transcript levels were found to be decreased and the father’s copy of the UBE3A gene was found to be expressing the UBE3A protein in many different parts of the brain and spinal cord of monkeys treated with these ASOs. 

This work marks a major milestone for the AS community and emphasizes the impact of patient advocacy groups, in this case FAST, on drug development for rare disorders.