Exploiting neural stem cell-targeted mouse models for improving the understanding of the pathogenetic mechanisms underlying Tuberous Sclerosis Complex and developing novel therapeutic approaches

Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, caused by mutations in either TSC1 or TSC2 genes. This disease mostly affects children, who develop hamartomas in different organs. Most patients display severe neurological manifestations, as intractable epilepsy, mental retardation and autism, which are intimately associated to peculiar lesions. Among these, epilepsy-inducing cortical tubers (CTs) and subependymal giant cell astrocytomas (SEGAs) are the major causes of morbidity. To date, preclinical modeling hasn't been successful in reproducing these two TSC-associated lesions. We recently generated and in-depth characterized novel mouse models of TSC, obtained by inducing the same genetic defect responsible for TSC in neural stem cells (NSCs) during embryonic development. These models recapitulate several distinctive neurological features of TSC, including cortical abnormalities and aberrantly expanded regions that closely resemble the static subependymal nodules (SENs), which often evolve into SEGAs in patients. However, none of these models show the presence of focal CTs or SEGAs. As such, to promote the development of CTs and SEGAs, we will exploit time-specific NSC-targeted mutant mice that will be also bred with tumor-prone mouse strains. These novel mouse models will be then exploited for testing potentially effective drugs, which might inhibit different pathways relevant for TSC pathogenesis. In the end, the availability of these different preclinical models will help us understanding further the molecular basis underlying TSC-associated neurological lesions, and will provide us with a powerful experimental platform to be exploited for testing candidate drugs.