Behavioral abnormalities, cognitive impairments, synaptic deficits, and gene replacement therapy in a CRISPR engineered rat model of the Cri du Chat syndrome-associated 5p15.2 deletion

The Cri du Chat Syndrome (CdCS), an untreatable genetic disorder, arises from a deletion on chromosome 5p. It manifests in distinct features, including a cat-like cry, facial abnormalities, microcephaly, and severe psychomotor/mental retardation. Lack of accurate animal models hinders research. We created a rat model with a similar deletion on chromosome 2q22 using CRISPR-Cas9, replicating CdCS's genetic aberration. This model exhibits deficits in social behavior, cognition, and anxiety. Our innovative gene replacement using AAV-Ctnnd2 via intravenous injection during early development mitigates cognitive impairments but not sociability or anxiety in CdCS rats. This study paves the way for gene therapy to tackle CdCS challenges.