Gene therapy: a promising treatment for Creatine Transporter Deficiency

Creatine Transporter Deficiency (CTD) is a rare genetic disorder linked to the X chromosome, caused by mutations in the SLC6A8 gene that encodes for the creatine transporter. Creatine plays essential physiological roles, most prominently in cellular energy buffering through the creatine/phosphocreatine system. In addition, it functions as a neuromodulator influencing both GABAergic and glutamatergic transmission, and exerts antioxidant and osmoprotective effects. Due to its hydrophilic nature, creatine relies on specific transport mechanisms to cross cellular membranes and the blood–brain barrier. Impairment of creatine transport results in cerebral creatine deficiency, leading to a clinical phenotype characterized by global developmental delay, intellectual disability, language impairment, autistic features, behavioural disturbances, and epilepsy. To date, there is no effective therapy available that can modify the course of CTD, and current treatments remain purely symptomatic, without restoring brain creatine levels. Therefore, the development and optimisation of therapeutic approaches represent a fundamental need that remains unmet. During my thesis period, we tested the FF351 plasmid both in vitro, ex vivo and in vivo. In vitro, we obtained moderate expression of the transporter, comparable to physiological levels. Through ex vivo experiments, we confirmed the presence of the transporter in the brain areas analysed. We measured physiological increases in creatine (Cr) levels, using GC-MS, following intracerebroventricular injection of the virus. In vivo, we obtained significant improvements in cognitive functions, assessed with Y-maze, Object Recognition Test (ORT) and Morris Water Maze (MWM).