FAST and FAST Canada are pleased to announce grant funding to David Segal, Ph.D. and his UC Davis lab to investigate targeting the Ube3a-AS (Ube3a Antisense Transcript) without disrupting the expression of Snord116 and Snord115.  Dr. Segal’s previously published research has shown that reduction in Ube3a-AS may also reduce expression of Snord116 and Snord115, which are needed for proper brain function.  Dr. Segal and his lab will test two novel methods to determine if they are able to target the Ube3a-AS without disrupting the expression of Snord116 and Snord115.  The first experiment will utilize an artificial transcription factor (ATF).  An ATF is a protein designed to target and modulate gene transcription.  For Angelman syndrome, artificial transcription factor therapy was originally designed to silence the expression of the Ube3a-AS (the “stop” on the paternal Ube3a allele) from its promoter (start of the transcription). Silencing the expression of Ube3a-AS would allow Ube3A to be expressed on the paternal allele. The UC Davis team will test an ATF made to “superactivate” the Ube3a gene directly, thereby hoping to overpower the blockade imposed by the Ube3a-AS, without disrupting Snord116 and Snord115 function.  They will also test a second, groundbreaking method using CRISPR technology to  precisely cut the Ube3a-AS without decreasing the expression of Snord116 and Snord 115.  This method could potentially result in a single dose, longer term solution for AS treatment via paternal gene activation.  With this grant, the UC Davis team will test these two strategies in AS rodents of multiple ages to understand their effectiveness in alleviating AS symptoms, and looking at, among other things, safety, dosing, and long-term effects.

Dr. David Segal is a UC Davis professor of Biochemistry and Molecular Medicine with joint appointments in the Genome Center, the MIND Institute, and the Department of Pharmacology.  His area of expertise is in gene editing.