A Human Targeted UBE3A-ATS Repressor
A FAST-TRAC Award
About the Grant
Angelman syndrome (AS) is caused by the loss of UBE3A protein expression in the neurons of the brain. Typically, one copy of the UBE3A gene is missing (deleted) or mutated (maternal), while the other copy of UBE3A (paternal) is functional but silenced, or turned off. This silencing is due to the presence of a long non-coding RNA that is preventing the expression of the UBE3A gene on the father's copy.
In prior FAST-funded work by this laboratory, the team demonstrated that they can make a therapeutic protein that can unsilence paternal UBE3A expression, restoring the functional Ube3a protein in the neurons of the brain and improve the symptoms in a mouse model of AS. This project is taking human neurons to find the right candidates to unsilence the paternal UBE3A gene. The goal is to rapidly screen through many designs of zinc finger proteins to get the one that is highly specific for unsilencing the human UBE3A gene, while not affecting other genes. The prior work in mice shows that this could be a potential therapeutic option for AS.
The Principal Investigator, David Segal, PhD
David Segal received his Ph.D. from the University of Utah, performed a post-doc at The Scripps Research Institute, and now serves as the Harold Albin Johnson Chair of Biochemistry and Molecular Medicine at UC Davis. His research focuses on the application of molecular therapy for neurodevelopmental disorders, including Angelman, ADNP, and other rare genetic conditions. His lab uses antisense oligonucleotides and CRISPR-based tools to modify gene expression in vivo. He is an AAAS fellow, an investigator in the NIH Somatic Cell Genome Editing Consortium, and Field Chief Editor of Frontiers in Genome Editing.