Editorial [Hot Topic:Drug Targets in Prion Diseases (Guest Editor: Hermann M. Schatzl)]

Prion diseases are strictly fatal neurodegenerative and infectious disorders in man and animal for which no effective therapeutic or prophylactic regimens are presently available. The underlying molecular mechanism is the conformational conversion of the normal cellular prion protein (PrPc) into the pathological isoform PrPSc, accompanied by dramatic changes in biochemical properties. Prion diseases are prototypic for conformational disorders, but are unique in its infectious character and still enigmatic in many aspects. The manifestation of human prion diseases can be acquired by infection, or endogenously as sporadic or genetic disease. Intra- and also inter-species transmission is frequent in animal diseases, with the risk of zoonotic diseases like recently seen with vCJD caused by BSE. vCJD seems rather effectively transmissible within the human population by blood products, resulting in iatrogenic secondary vCJD. The disease itself is restricted to the central nervous system and therefore difficult to diagnose pre-clinically. As prions propagate by conversion of a host-encoded protein, an immune reaction in the host is completely absent and serological markers are missing. This self-tolerance hampers classical prophylactic approaches, e.g. in form of vaccines. Very challenging is also treatment of prion diseases, which asks for compounds able to effectively cross the blood-brain-barrier. The non-availability of means for pre-clinical diagnosis results in advanced stages of brain damage when clinical symptoms become evident. Nevertheless, in animal models a very impressive reversion of pathology and clinical symptoms could be achieved. Although human forms of disease are rare, with an incidence of one in a million world-wide for sporadic CJD, and animal diseases do not really ask for therapy, there is an urgent need for postexposure, therapeutic and eventually prophylactic intervention possibilities, in particular with regard to vCJD and the fact that this is a strictly deadly disease. In this article series, recent advances in therapeutic developments, novel molecular targets, and future perspectives are discussed. Obvious target groups are PrPc and PrPSc themselves, required as functional substrate or template, respectively, for prion conversion. Many intervention strategies address the interaction and the subsequent conversion process of isoforms. Other targets are the cellular clearance capacity for PrPSc, the involvement of putative co-factors, and the neurotoxic effects exerted by yet to characterize toxic PrP species. Finally, experimental proof-of-principle exists for active and passive vaccination strategies. Although various promising drug candidates with anti-prion activity have been identified, this solid proof-of-concept could not yet be transferred into translational medicine.