Gene therapy strategy to treat Cornelia de Lange syndrome due to Hdac8 Deficiency

Cornelia de Lange syndrome (CdLS) is a rare, multi-system genetic disorder characterized by developmental and cognitive impairments with systemic manifestations. Among the genes associated with CdLS, loss-of-function variants in HDAC8 account for approximately 4% of cases (referred to as CdLS5), causing the dysregulation of the cohesin complex, a core pathogenic mechanism of the disorder. Currently, no gene-based therapeutic strategy exists to directly address CdLS resulting from HDAC8 deficiency. Here, we created a new CdLS5 mouse model by introducing a clinically reported HDAC8 p.Ile19Ser variant in the mouse Hdac8 gene using CRISPR-Cas9 technology. Comprehensive molecular, morphological, and behavioral characterization revealed that the new Hdac8I19S mouse strain exhibits a robust phenotype, including marked alterations in deacetylase activity and pronounced developmental and behavioral deficits. This model was subsequently used to evaluate a gene augmentation approach aimed at increasing HDAC8 protein levels and restoring cohesin function through delivery of human HDAC8 transgene. Two AAV vectors driving expression of human HDAC8 were assessed. Although efficient delivery and robust expression were achieved, only modest effects on Smc3 acetylation, a key HDAC8 substrate, were observed, and no significant improvement in cognitive or behavioral phenotypes was detected. Overall, these findings demonstrate that postnatal HDAC8 gene augmentation resulted in limited biochemical correction and minimal phenotypic improvement under the conditions tested. These results highlight important biological considerations, including target engagement and developmental timing, that should be considered in the development of effective therapies for cohesin-related disorders.