In vivo base editing of Chd3 rescues behavioural abnormalities in mice - PubMed
4 days ago
- #gene editing
- #CHD3
- #neurodevelopmental disorders
- Neurodevelopmental disorders caused by mutations in chromatin-remodelling genes lack targeted treatments.
- Snijders Blok-Campeau syndrome (SNIBCPS) is caused by pathogenic variants in CHD3, leading to intellectual disability, autistic-like behaviours, and motor deficits.
- A humanized mouse model (Chd3hR1025W/+) with the CHD3 variant p.R1025W recapitulates SNIBCPS features, including reduced CHD3 protein levels and behavioural abnormalities.
- A TadA-embedded adenine base editor (TeABE) was engineered and delivered brain-wide using a dual AAV system, achieving efficient A•T-to-G•C correction with minimal bystander activity.
- The intervention restored CHD3 levels and improved behavioural abnormalities in mice.
- Intrathecal dual AAV delivery in nonhuman primates showed widespread neuronal transduction and efficient TeABE reconstitution, supporting translational feasibility.
- In vivo base editing is a viable therapeutic approach for CHD3-related neurodevelopmental disease and offers a framework for treating monogenic neurodevelopmental disorders.