Maria T Clarke, Laura Remesal, Lea Lentz, Danielle J Tan, David Young, Slesha Thapa, Shalini Namduri, Beltran Borges, Georgia Kirn, Jasmine Valencia, Manuel E Lopez, Jan H Lu, Lawrence R Shiow, Scott Dindot, Saul Villeda, Stephan J Sanders, Tippi C MacKenzie
Angelman Syndrome, an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution...
February 6, 2024: Molecular Therapy