Research objectives and content
Taking into account that the two relevant organs involved in the replication of the TSE agents (or priors) and accumulation of PrPsc (prion protein scrapie) are the spleen and the brain, we have conceived two approaches, based on the use of nanoparticles of chitosan as drug delivery systems, for contributing to the comprehension of the prion diseases:- the first aim consists in the evaluation of the effects induced by the selective targeting to the spleen of compounds which are supposed to inhibit the accumulation of the PrPsc:- Inhibition of PrP synthesis by an antisense oligonucleotide strategy. - Inhibition of Prpsc accumulation (transconformation?) by polyene antibiotics. - Destruction of target cells supporting PrPsc accumulation in spleen with clodronate.- the second one is to investigate in vivo the role of the microglial cells in the pathogenesis of TSEs. These cells have been proven to be indispensable for neuronal toxicity of PrPsC in vitro and a strategy of depletion will be used in vivo. The working system will be to engraft murine embryonic nervous system hyperexpressing PrP in the brain of mice lacking PrP. The graft tissue will be depleted in vitro for microglial cells with LLME (L-leucin methyl ester) or clodronate before grafting. The microglial depletion will then be maintained in vivo by the delivery of the same molecules with drug carrier systems.This research proposal could also open new perspectives for the pharmacological treatment of scrapie in experimental models.
Training content (objective, benefit and expected impact)
The use of targeted nanoparticulate formulations able to deliver anti-PrP oligonucleotides and other anti-PrP compounds to the brain and to the spleen may allow to highlight some crucial aspects of the pathogenetical mechanisms involved in prion diseases. This research could open new perspectives for the pharmacological treatment of prion diseases. Moreover, this research project will lead to progress in drug delivery systems, especially in the new nanoparticulate formulations for brain delivery. This would represent a major step ahead not only for the treatment of prion diseases but also of other neurodegenerative conditions including Alzheimer's disease. In addition, formulations for oligonucleotide delivery to humans may emerge from the proposed research.