Researchers used genome editing in a mouse model to correct CHD3 gene variants that, in humans, cause a rare neurodevelopmental disorder, and were able to alleviate disease-related symptoms. The authors of a study published in Nature applied a base-editing strategy, a highly precise genetic tool that can swap a single faulty DNA base for the correct one without cutting the DNA strand.

The protein encoded by CHD3 is a chromatin remodeler and thus plays a key role in regulating gene expression. During brain development and in mature neurons, CHD3 controls genes involved in axon guidance, synapse formation and neuronal maturation.

In humans, variants in CHD3 underlie the rare Snijders–Blok–Campeau syndrome, which is associated with developmental delay, intellectual disability, autism-like behavioural features and motor impairments. In the study, the researchers first generated a “humanized” mouse model carrying a common dominant missense mutation (p.R1025W) in CHD3. These mice had reduced levels and impaired function of the CHD3 protein and they showed key features of the disorder, including altered social communication, cognitive deficits and motor abnormalities.

The team then delivered their specially engineered base editor (TeABE) into the mouse brain using two adeno-associated viral vectors and subsequently observed efficient correction of the mutation across several brain regions, with only minimal unwanted changes at the neighbouring bases. Following this correction, CHD3 protein levels increased and the animals’ behavioural abnormalities improved markedly – despite the fact that treatment was administered to the postnatal, developed brain. The work thus provides important evidence that highly targeted single-base correction in the postnatal brain modified the cause of a monogenic neurodevelopmental disorder.