Prion protein-specific antibodies for therapeutic intervention of transmissible spongiform encephalopathies.
ABSTRACT Prion diseases, also called transmissible spongiform encephalopathies, are a group of fatal neurodegenerative conditions that affect humans and a wide variety of animals. There is no therapeutic or prophylactic approach against prion diseases available at present. The causative infectious agent is the prion, also termed PrPSc, which is a pathological conformer of the cellular prion protein PrPC. Passive immunisation studies with PrPC-specific antibodies indicated that immunotherapeutic strategies directed against PrPC can prevent prion disease. In this review, putative mechanisms of antibody-mediated prion inactivation, as well as active immunisation strategies, are discussed. Special attention is given to the problem of immunological self-tolerance against PrP.
Article: Therapies for human prion diseases.[Show abstract] [Hide abstract]
ABSTRACT: The pathological foundation of human prion diseases is a result of the conversion of the physiological form of prion protein (PrP(c)) to the pathological protease resistance form PrP(res). Most patients with prion disease have unknown reasons for this conversion and the subsequent development of a devastating neurodegenerative disorder. The conversion of PrP(c) to PrP(res), with resultant propagation and accumulation results in neuronal death and amyloidogenesis. However, with increasing understanding of neurodegenerative processes it appears that protein-misfolding and subsequent propagation of these rouge proteins, is a generic phenomenon shared with diseases caused by tau, α-synucleins and β-amyloid proteins. Consequently, effective anti-prion agents may have wider implications. A number of therapeutic approaches include polyanionic, polycyclic drugs such as pentosan polysulfate (PPS), which prevent the conversion of PrP(c) to PrP(res) and might also sequester and down-regulate PrP(res). Polyanionic compounds might also help to clear PrP(res). Treatments aimed at the laminin receptor, which is an important accessory molecule in the conversion of PrP(c) to PrP(res) - neuroprotection, immunotherapy, siRNA and antisense approaches have provided some experimental promise.01/2013; 2(3):176-186.
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ABSTRACT: Prion diseases (e.g., Creutzfeldt-Jakob disease in humans) are always fatal neurodegenerative disorders characterized by conversion of the ubiquitous cellular prion protein (PrP(c)) into a pathological conformer. Immunological strategies are considered as promising prophylactic or therapeutic approaches but, unfortunately, vaccination attempts until now have been very disappointing in wild-type animals because of immune tolerance to self PrP(c). Encouraging results have come from recent experiments carried out through genetic immunization (i.e., injection in mice of cDNA coding for murine prion protein [PrP]) or heterologous protein immunization (i.e., injection in mice of PrP from another species), albeit the levels of autoantibodies in wild-type animals remained generally low. Here we investigated whether combining the potential benefits of these two last approaches, namely using genetic immunization with the cDNA coding for a heterologous PrP, could more efficiently break immune tolerance. Wild-type mice were thus vaccinated with cDNA coding for human PrP(c), fused or unfused to a stimulatory T-cell epitope, using or not using electrotransfer of DNA. After three DNA injections, mice receiving electrotransferred DNA developed a strong immune response, oriented toward the humoral Th2 type, characterized not only by high IgG1 and IgG2a antibody titers against the heterologous human PrP(c), but also, as expected, by significant amounts of autoantibodies recognizing the native conformation of murine PrP(c) expressed on cell membranes as revealed by flow cytometry and immunofluorescence. These results hence open the way for investigation of the possible protective effects of anti-PrP(c) autoantibodies in infected mouse models. More generally, our results suggest that this original immunization strategy could be of value for circumventing tolerance to poorly immunogenic proteins.DNA and cell biology 12/2009; 29(3):121-31. DOI:10.1089/dna.2009.0940 · 1.99 Impact Factor
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ABSTRACT: Since the appearance in 1986 of epidemic of Bovine Spongiform Encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programmes in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of Transmissible Spongiform Encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed.Prion 09/2013; 7(5). DOI:10.4161/pri.26533 · 1.97 Impact Factor