Engineered adeno associated-viruses expressing anti-prp molecules and polyelectrolyte gold nanoparticles as new therapeutic strategies for prion diseases in mouse models

The prion diseases are neurodegenerative disorders of humans and animals that are sporadic or inherited in origin and can be transmitted. Despite remarkable differences in phenotypic expression, these disorders share a similar pathogenic mechanism, i.e. a posttranslational modification of the prion protein from a normal cellular isoform (PrPC) to insoluble and protease-resistant disease-specific species (termed PrPSc). PrPSc accumulates in the brain and, according to prion hypothesis, is responsible for the propagation of the pathologic process and transmissibility of the disease, by converting PrPC into a likeness of itself. In a model of prion replication, direct interaction between PrPSc template and the endogenous PrPC is proposed to drive the formation of nascent infectious prions. For these reasons therapies to prevent prion diseases can be targeted towards the selective binding of PrPC or PrPSc and the process of conversion. Many compounds have been proposed as potential therapies in the treatment of prion diseases. With the development of novel gene delivery system and nanomedicine, it has been possible to design innovative in vitro therapies effective in cure chronically prion infected cells. ScFvD18, an antibody fragment composed by the variable regions of the heavy and light chains, already resulted in efficient clearing PrPSc in prion infected cells. Fo this reason, ScFvD18 was engineered in Adeno-Associated Viral vectors (AAVs) serotype 9 (AAV9-ScFvD18) and inoculated into the brain of prion infected mice to assess its effectiveness in modify disease progression. Also polyelectrolyte covered gold nanoparticles (AuNPs) are excellent therapeutic compounds due to the intrinsic properties as being non-toxic, inert to most chemical reactions and easy to prepare. In vitro experiments showed that even picomolar amount of AuNPs with layer-wise deposition of oppositely charged synthetic polyelectrolytes, such as polyallylamine hydrochloride (PAH)and polystyrenesulfonate (PSS), were able to hamper the accumulation of PrPSc in cell culture. The efficacy of these nanogold particles was further assessed in prion infected mice.