In Vivo Base Editing of CHD3 Rescues Behavioural Abnormalities in Mouse Model

In vivo base editing corrected a disease-causing mutation in the CHD3 gene and rescued behavioural abnormalities in a humanized mouse model of Snijders Blok–Campeau syndrome (SNIBCPS), a neurodevelopmental disorder caused by pathogenic variants in CHD3. The study engineered a TadA-embedded adenine base editor (TeABE) and delivered it brain-wide using a dual adeno-associated virus (AAV) system, restoring CHD3 protein levels and ameliorating deficits in social communication, cognition and motor coordination. These findings establish in vivo base editing as a viable therapeutic approach for CHD3-related neurodevelopmental disease and demonstrate that precise single-base correction in the postnatal brain can restore protein dosage and function.

SNIBCPS is an autosomal-dominant disorder first described in 2018, with more than 100 cases reported. It manifests with intellectual disability, autistic-like behaviours, motor deficits, and is frequently accompanied by autism spectrum disorder. Most cases are caused by single-nucleotide variants; the recurrent variant p.R1025W accelerates CHD3 protein degradation. The researchers generated a humanized mouse model (Chd3hR1025W/+) that recapitulated key features of the syndrome, including reduced CHD3 protein levels and abnormalities in social communication, cognition and motor coordination.

The team engineered TeABE to convert the mutant A•T base pair to G•C and delivered it to the brain using a dual-AAV system via intravenous injection, an approach that enabled effective penetration across the blood–brain barrier. They achieved efficient on-target A•T-to-G•C correction across multiple cortical and hippocampal regions with minimal bystander activity. TeABE editing restored CHD3 levels and ameliorated behavioural abnormalities in the mice.

In nonhuman primates, intrathecal delivery of AAV9 vectors encoding TeABE achieved broad brain transduction and editor reconstitution, supporting translational feasibility.

Base editing is an optimized approach that enables precise single-base editing without DNA double-strand breaks, a limitation of CRISPR–Cas9. Adenine base editors convert A•T to G•C. The authors note that base-editing gene therapy has previously shown success in Hutchinson–Gilford progeria syndrome, spinal muscular atrophy, ASD, and genetic heart and retinal disease in mouse models, offering a framework for the treatment of monogenic neurodevelopmental disorders.