Prion diseases are rare, progressive, and incurable neurological disorders that naturally afflict both humans and animals, with the former including Creutzfeldt−Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia (FFI).

Decades of research have determined that these disorders share a common molecular mechanism: the conversion of the cellular prion protein (PrPC) into an infectious form (PrP scrapie, PrPSc) that accumulates in the brain affected individuals. Notably, a great deal of evidence suggests that PrPC has a critical role in supporting PrPSc propagation and transducing its neurotoxicity.

For the past five years, we have employed a previously developed highly robust and quick assay to search for compounds capable of suppressing PrPC-mediated toxicity. Thanks to this method, called drug-based cell assay (DBCA), we developed a class of drug-like molecules capable of counteracting prion toxicity. In particular, the most promising derivative (Mol101) showed potent activity in cell and mouse brain slice models of prion diseases.

In light of these promising results, our project aims at evaluating the therapeutic efficacy of Mol101 in a new mouse model for inherited CJD. Our study will be instrumental in reaching a reliable conclusion regarding the possible translation of these therapeutics in prion disease patients.