SiRNA targeting of UBE3A-ATS in human and mouse Angelman Syndrome models
SiRNA targeting of UBE3A-ATS in human and mouse Angelman Syndrome models
Chemically modified divalent silencing RNA’s (di-siRNA’s) are potent oligonucleotide based therapeutics potentially capable of widespread brain distribution and prolonged target gene silencing. The goal of this project is to identify candidate di-siRNA’s that can silence the paternal UBE3A antisense transcript, which typically silences the expression of the paternal UBE3A gene. The goal is that this may allow for re-expression of the paternal UBE3A gene. The team will use pluripotent stem cell-derived neurons from Angelman syndrome (AS) patients and mouse primary neurons to screen and identify human and mouse candidate di-siRNA’s, respectively. Identified mouse candidate di-siRNA’s will then be injected into the brain of the AS mouse model to test their efficacy in re-expressing paternal Ube3a and safety. These studies are critical for determining the feasibility of this approach and, if promising, will support further preclinical testing to potentially develop this technology into a future therapeutic.
Principle Investigator
Mark Deehan, PhD
Dr. Mark Deehan is an Instructor at MassGeneral Hospital and Harvard Medical School in the laboratory of Dr. Marian DiFiglia and an associated faculty at the MGH Lurie Center for Autism. Dr. Deehan received his Ph.D. from Boston University in 2019 studying host-pathogen interactions in the fruit fly. In 2020, Dr. Deehan transitioned to Dr. DiFiglia’s laboratory for his postdoctoral studies where he extensively characterized the first mouse model and first human pluripotent stem cell model of the newly discovered NACC1 neurodevelopmental disorder. Ongoing research efforts focus on understanding the molecular function of NACC1 in brain development and the NACC1 disorder and collaborating to develop divalent silencing RNA’s and base editor gene therapies for NACC1. With the support of FAST, Dr. Deehan and his collaborators are applying the divalent silencing RNA technology to silence the paternal UBE3A antisense non-coding RNA and re-express the paternal UBE3A protein.
