Preclinical Development of Brain-Penetrant Compounds Halting Prion Neurotoxicity

Prion diseases are rare brain disorders that can affect both humans and animals. In humans, these disorders include Creutzfeldt−Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and Fatal Familial Insomnia (FFI). The diseases can have a genetic origin, be transmitted horizontally, or manifest spontaneously. All forms of prion diseases share a common pathogenic mechanism: the conversion of a normal protein called PrP into a toxic form called PrPSc. PrPSc can propagate as an infectious agent by converting PrP molecules located on the surface of neuronal cells into PrPSc. As a result, PrPSc accumulates in the brain and causes neuronal death. A similar mechanism occurs in genetic forms of prion diseases when specific mutations alter the stability and function of PrP. We have employed a novel laboratory test to identify chemical agents that can counteract the toxicity of mutant PrP molecules. Over the past seven years, our group has worked to improve these chemicals to make them suitable for prion disease patients. However, before achieving such a goal, we need to further enhance these molecules' pharmacological properties and demonstrate their effectiveness in animal models of prion diseases. This project is precisely focused on achieving these goals.