A new exploitation of a tetracationic-porphyrin able to reduce PrPC and to inhibit PrPSc replication: characterization of the mechanism of action and preclinical studies in mouse models of genetic prion disease

Prion diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Stra¨ussler Scheinker (GSS) syndrome, fatal familial insomnia (FFI) in humans, mad cow disease, and scrapie of sheep, are invariably fatal neurodegenerative disorders for which there is no effective therapy. These diseases arise from the conformational conversion of a single normal protein of the brain (cellular prion protein, PrPC) to an altered disease-specific form (scrapie prion protein, PrPSc) that spreads in the brain by converting other PrPC molecules. Accumulation of PrPSc in the brains of the patients causes abnormal proliferation of certain cells of the brain (gliosis), holes in the brain tissue (spongiosis), and loss of neurons (neurodegeneration), leading to dementia, motor dysfunction and other neurophysiological deficits, such as insomnia. Prion diseases can be sporadic, infectious or genetically inherited. Genetic prion diseases are due to mutations in the PrP gene, which favor the spontaneous conversion of PrPC to PrPSc. Possible therapeutic strategies for prion diseases include reducing PrPC level, thus eliminating the substrate for PrPSc formation, and blocking the conversion of PrPC into PrPSc. We have found that a particular molecule, named Zn(II)-BnPyP, does both: it eliminates PrPC (wild-type or mutant) form cells and inhibits the conversion of PrPC to PrPSc. The aim of the present study is to characterize the mechanism of action of Zn(II)-BnPyP and to test whether it can prevent or cure disease in mouse models of genetic CJD, GSS and FFI. We hope that our study will contribute to develop an effective therapy for these devastating disorders.