The main current research line is focused on understanding the molecular and cellular mechanisms underlying neurodevelopmental disorders, with particular emphasis on CDKL5 Deficiency Disorder (CDD), considered a variant of Rett syndrome. The ultimate goal is to identify and develop therapeutic strategies capable of improving the severe cognitive impairment that characterizes these conditions.
CDKL5 Deficiency Disorder is a severe developmental encephalopathy that predominantly affects females. It is caused by mutations in the CDKL5 gene, located on the X chromosome, leading to the absence or loss of function of the CDKL5 kinase. Patients with CDD present a complex clinical phenotype that includes early-onset epilepsy (within the first months of life), intellectual disability, autism spectrum features, visual and motor impairments, and gastrointestinal dysfunction. Most affected individuals do not acquire the ability to walk, speak, or feed independently. To date, approximately 10,000 patients with CDKL5 mutations have been identified worldwide; however, due to limited awareness of the disorder, many cases are likely still undiagnosed. Currently, there are no disease-modifying treatments for CDD, and clinical management is mainly focused on symptomatic care and family support. Therefore, the development of effective therapies represents a major clinical and societal challenge.
The overall objective of our research is to correct the neurodevelopmental alterations observed in a murine model of CDD through therapeutic strategies aimed at restoring CDKL5 protein function. To this end, we are developing and evaluating innovative approaches, including protein replacement therapy and gene therapy strategies.
The protein replacement approach involves the systemic administration of a recombinant CDKL5 protein produced in vitro and engineered to cross the blood–brain barrier and reach the brain tissue, thereby directly restoring protein function in neuronal cells.
The gene therapy strategy is based on the use of viral vectors to deliver to the brain the genetic material encoding a secretable form of the CDKL5 protein. Once produced by the transduced cell, this protein can be released and subsequently taken up by neighboring cells, potentially enhancing therapeutic efficacy compared to conventional gene therapy approaches.
The ongoing studies are aimed at the preclinical validation of these strategies and at the development of therapeutic approaches that may be translatable to humans, ultimately paving the way for future clinical trials.
