A high-fidelity RNA-targeting Cas in an adeno-associated virus vector restores paternal Ube3a expression and improves Angelman Syndrome in mice

Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. Here, we found that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPT/Cas13x (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in wild-type primary cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter-driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to four months post treatment.