Behavioral Improvement Through In Vivo Base Editing in a Mouse Model of Snijders Blok-Campeau Syndrome

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Abstract

Snijders Blok-Campeau Syndrome (SNIBCPS) is a rare neurodevelopmental disorder caused by mutations in the CHD3 gene. Here, we report a de novo single-nucleotide variant (c.C3073T, p.R1025W) in CHD3 identified in a child with SNIBCPS, which leads to accelerated degradation of the CHD3 protein. Using a Chd3 R1025W/+ knock-in mouse model, we observed impaired vocalization, cognition, and autism-like behaviors. To address these deficits, we developed an improved TadA-embedded adenine base editor (TeABE) and delivered into the mouse brain via Adeno-associated virus (AAV). Base editing in vivo significantly restored CHD3 protein levels in the mouse brain and ameliorated various behavioral abnormalities. Furthermore, we validated the AAV-mediated delivery efficacy of TeABE in nonhuman primate, highlighting its translational potential. These findings establish in vivo base editing as a promising therapeutic strategy for SNIBCPS and pave the way for clinical applications targeting brain disorders.

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