PHARMACOLOGICAL TREATMENT WITH SELICICLIB IMPROVES COGNITIVE AND NEUROANATOMICAL DEFECTS IN A MOUSE MODEL OF THE CDKL5 DEFICIENCY DISORDER

CDKL5 deficiency disorder (CDD) is an ultra-rare neurodevelopmental condition mainly affecting females. Symptomatology includes early-onset epileptic seizures, intellectual disability and motor impairments. No cure exists. CDD is caused by mutations in X-linked cyclin-dependent kinase-like five (CDKL5) gene, encoding a serine/threonine kinase highly expressed in the brain. Studies on CDD mouse models and patient-derived induced pluripotent stem cell neurons revealed profound alterations in neuronal morphology and dendritic spine maturation. Although the underlying mechanisms remain unclear, accumulating evidence points to a potential pathogenic role of brain cytoskeleton dynamic defects in CDD. Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase whose dysregulation is implicated in neurological disorders sharing key clinical features with CDD, is a key regulator of neuronal cytoskeletal dynamics. In this study, we investigated whether treatment with seliciclib, a small-molecule with high inhibitory potency for Cdk5 and currently under clinical evaluation for five different indications, could rescue behavioral, neuroanatomical and peripheral oxidative alterations in a CDD mouse model. Fully symptomatic female heterozygous Cdkl5 knockout (Cdkl5-Het) mice and wild-type littermates were treated with intraperitoneal injections of seliciclib (50 mg/kg) or control solution for 14 consecutive days. A battery of behavioral tests and subsequent brain and blood analyses were conducted to evaluate treatment efficacy. Systemic seliciclib administration in Cdkl5-Het mice significantly improved spatial reference and working memory deficits, rescued hippocampal dendritic spine maturation, ameliorated cytoskeletal-related brain molecular alteration and normalized peripheral oxidative stress in whole blood. These findings support the therapeutic potential of seliciclib for CDD, highlighting its relevance as a drug-repositioning strategy. ^{Funded-by-CDKL5-Insieme-verso-la-Cura-Association.}