Prion diseases are lethal for both humans and animals, and affected individuals die after several months following a rapid disease progression. Although researchers have attempted for decades to develop effective therapeutics for the therapy of human prion disorders, until now no efficient drug has been available on the market for transmissible spongiform encephalopathy (TSE) treatment or cure. Approximately 200 patients worldwide have died or suffer from variant Creutzfeldt-Jakob disease (CJD). Incidences for sporadic and familial CJD are approximately 1.5-2 per million per year and one per 10 million per year, respectively, in Europe. This review summarizes classical and modern trials for the development of effective anti-TSE drugs, introduces potential effective delivery systems, such as lentiviral and adeno-associated virus systems for antiprion components, including antibodies and siRNAs, and presents vaccination trials. Most of the antiprion drugs target prion protein PrP(c) and/or PrP(Sc). Alternative targets are receptors and coreceptors for PrP, that is, the 37/67-kDa laminin receptor and heparan sulfate proteoglycanes. We review clinical trials for the treatment of TSEs and describe hindrances and chances for a breakthrough in therapy of prion disorders.

16Transmissible spongiform encephalopathies known as prion diseases are a group of 17 fatal neurodegenerative disorders that affect both humans and animals. The generally 18 accepted principle of the disease is that the conversion of the cellular prion protein (PrP c ) into 19 the disease associated isoform PrP Sc leads to spongiform degeneration of the brain and 20 amyloid plaque formation. Until now no therapy leading to potential alleviation or even cure 21 of the disease exists. It is important to develop therapeutic approaches for the treatment of 22TSEs since these infections are inevitably fatal and, especially in the case of vCJD, they 23 affect youngsters. Besides current conventional therapeutic strategies, this review summarizes 24 new therapeutic tools targeting the prion receptor LRP/LR. 25 26

The 37 kDa/67 kDa laminin receptor LRP/LR acts as a receptor for both PrPc and PrPSc at the cell surface. Here, we further analyzed the subcellular localization of fluorescent labeled prion protein (PrP) and laminin receptor (LRP/LR) molecules. We show that EGFP-PrP is localized at the cell surface and in a perinuclear compartment, respectively. In contrast, a DsRed-DeltaSP-PrP mutant lacking the signal peptide is almost exclusively found in the nucleus but does not colocalize with heterochromatin. Interestingly, LRP-DsRed efficiently colocalizes with EGFP-PrP in the perinuclear compartment and LRP-ECFP partly colocalizes with DsRed-DeltaSP-PrP in the nucleus, respectively. We conclude that the interactions of PrP and LRP/LR are not restricted to the cell surface but occur also in intracellular compartments suggesting a putative role of LRP/LR in the trafficking of PrP molecules.