(300 WORDS MAX.) In frontotemporal dementia (FTD) and Alzheimer's disease, aggregation of the tau protein into fibrillar tangles causes brain degeneration and progressive cognitive decline. Blocking tau aggregation could slow or halt the progression of disease. Drawing from a decade of research on the structures of aggregated proteins and licensed proprietary approaches, ADRx has developed a set of novel polypeptide-based tau aggregation inhibitors (TAIs). These molecules are designed to bind to the segments of tau that drive its aggregation, thereby blocking their ability to self-associate. ADRx has shown that these TAIs reduce aggregation of multiple forms of tau in biochemical assays and aggregation of tau inside cells. ADRx has brought together a purpose-built team and set of technologies to evaluate these TAIs. ADRx scientists, along with Ben Deverman (Caltech) and Ken Kosik (UCSB), have designed and implemented a pilot experiment to test whether a uniquely engineered virus can enable the brain expression of these TAIs and alter the course of neurodegeneration in a mouse model of FTD. Our pilot study has demonstrated that our TAI can indeed alter pathology in this mouse model of tauopathy. We have been able to significantly reduce tau aggregation broadly within the brain and specifically in regions known to degenerate in FTD and AD. These achievements encourage further testing of these molecules. Here we propose testing our 1st generation virus and a novel 2nd generation virus in a mouse model of FTD caused by a P301S mutation in tau. The proposed studies will be more detailed in nature than the completed pilot study, evaluating both prevention of tau pathology and behavioral abnormalities in the disease model. This will give ADRx and the field additional confidence in the potential clinical value of TAIs and the potential of viral therapies.