Creatine Deficiency Syndrome: novel insight into brain function and therapeutic strategies

Creatine transporter deficiency (CTD) is an X-linked inherited metabolic disease presenting with cerebral creatine (Cr) deficiency, early intellectual disability, autistic behaviour and epilepsy. Although rare, CTD is a severe health care problem since it is a chronic condition with a strong impact on patients' quality of life. There is no cure for this disorder. Despite a good knowledge of the natural history of CTD and the role of Cr in energy metabolism, little is known about brain alterations underlying the impairment of multiple behavioural and cognitive domains in CTD. This project aims to explore how brain circuits are affected by Cr depletion and to develop gene therapy strategies to treat the symptoms associated with CTD. By integrating imaging and electrophysiological techniques in the murine model and patients, we will provide a unique characterization of the morphological and neurofunctional alterations of CTD brain. Most of our efforts will be devoted to testing a possible therapeutic strategy for CTD. In particular, we will evaluate a gene therapy approach aimed at modifying cell dysfunction by exogenous provision of a functional copy of the Cr transporter (CrT) gene in a well-established CTD mouse model. We will use the knowledge acquired so far on the mouse model to test this experimental product for the restoration of the physiological levels of Cr and ATP, the improvement of brain function, the suppression of the epileptic phenotype and the recovery of a correct balance within the neuronal circuits. We aim to demonstrate the feasibility of replacing the CrT protein in the mouse model and the reversibility of the CTD phenotype, laying the groundwork for the future development of CTD gene therapy approaches.