INNOVATIVE STRATEGY TO ENHANCE THE EFFICIENCY AND SAFETY OF GENE THERAPY FOR CDKL5 DEFICENCY DISORDER

CDKL5 deficiency disorder (CDD) is a rare and severe genetic neurodevelopmental disorder that is caused by mutations in a single X-linked gene, which encodes CDKL5. This protein is mainly expressed in neuronal cells. The mutations lead to the absence of CDKL5, resulting in a severe pathology characterized by intellectual disability, motor impairment, visual deficits, and early-onset epilepsy. Currently no therapy is available for CDD. For a monogenic disease such as CDD, therapeutic approaches based on the delivery of a healthy copy of the mutated gene to cells which lack functional protein represents the most curative approach. Nowadays, there are encouraging proof-of-concept studies that demonstrate the potential effectiveness of the gene therapy approach for these pathologies, but also highlight significant caveats regarding the low efficiency of gene delivery to the brain by viral vectors, and risk of toxic side effects connected with the usage of large vector doses. The aim of this study is to improve gene therapy approach for CDD, enhancing its efficiency and safety. This will be achieved through an innovative strategy of gene therapy that allows the usage of lower doses of viral vectors while ensuring a wide distribution of the therapeutic protein to neuronal cells. The effectiveness of this new approach will be compared with that of the classical approach in animal models of the pathology. We believe that this study, in addressing the potential impact of an innovative approach of gene therapy, might open an avenue to a cure not only for patients with CDD but also may become a powerful tool for the cure of other monogenic diseases.