Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration - PubMed
3 days ago
- #NmCas9 nickase
- #Angelman syndrome
- #AAV gene therapy
- The study demonstrates the use of nickase NmCas9 (nNmCas9-D15A) to unsilence paternal Ube3a in a mouse model of Angelman syndrome, a neurodevelopmental disorder caused by loss of maternal UBE3A.
- Unlike previous methods using active nucleases that create DNA double-strand breaks and risk AAV vector integration, this approach avoids these safety concerns by targeting the non-template strand of Ube3a-ATS without generating DSBs.
- AAV9 delivery of nNmCas9-D15A in mice led to durable reduction of Ube3a-ATS and elevated Ube3a expression in the cerebral cortex and hippocampus for at least 6 months, restoring UBE3A in about 87% of cortical neurons with high efficiency.