Preparing to treat prions

Those of us who live on an island affected by a small number of emotive cases of variant CreutzfeldJakob disease (vCJD) would be delighted if a safe and effective treatment became available for this devastating disease. What are the prospects? Prion diseases result from the mis-folding of a normal cellular protein (PrP) to form a pathogenic isoform (PrP) [1]. Understanding of pathogenesis of prion diseases has improved in the last decade due, in no small part, to the use of cleverly designed mouse experiments and transgenic mouse models. In summary, they reveal that: 1) the PrP gene is required for susceptibility to disease and for replication of prions [2]; 2) pathogenic human alleles of PrP induce spontaneous spongiform change [3]; 3) in animals with more than one PrP gene, distinct inocula are enciphered so that they preferentially produce copies of themselves [4]; 4) in PrP knockout mice intracerebral PrP+ neurografts confer susceptibility to intracerebral but not intraocular or peritoneal inoculation of prions [5,6]; 5) addition of a bone marrow transplant to PrP knockout mice with intracerebral PrP+ neurografts allows infectivity to reach the spleen but not the brain; B cells are an important component of the bone marrow transplant which mature follicular dendritic cells, but do not themselves have to be PrP+ [6–8]; 6) complement, or complement receptors, plays a role in augmenting the infectivity of low dose inocula for the spleen [9]; 7) transmission from the spleen to the CNS may involve the splanchnic and vagus nerves [10–12]. Short of re-populating the world with PrP gene knockout humans, how can all this information be used to reduce the impact of vCJD? First, an antiprion compound could stabilise the PrP in its native form within a cell analogous to what is achieved naturally by PrP polymorphisms which confer resistance to scrapie. Using the spatial orientation and basic nature of four such dominant negative polymorphisms, a computational search from over 200,000 known chemical moieties identified a lead compound and derivatives which have micromolar activity [13]. Furthermore, since the transition from native to pathogenic isoform is accompanied by a dramatic increase in beta-sheet from 3% to 40%, peptides (termed ‘beta breakers’) containing at least one proline residue can decrease the probability of such a transition and reduce the infectivity of an inoculum when added in vitro prior to inoculation [14]. Recent results show that quinacrine or chlorpromazine can reduce the conversion of PrP to PrP [15]. Second, a compound could bind to the abnormal isoform and promote its degradation. This appears to be the mechanism for polyamines [16] or suramin which co-localise with PrP in secondary lysosomes and render this pathogenic isoform susceptible to proteases [17]. It may also explain the action of antibodies which bind to cell surface PrP of cell cultures and clear pre-existing PrP [18]. Third, a compound could reduce the transmission of the abnormal isoform within the body. For example, soluble lymphotoxin B receptor can inhibit follicular dendritic cells thereby impeding the dissemination of PrP [19] while having no effect when scrapie is inoculated intra-cerebrally [20]. Likewise, depletion of complement (or blockade of complement receptors) might decrease infectivity reaching the spleen [9]. The availability of prototype compounds acting in these distinct ways offers the potential of exploiting their effects synergistically. However, by acting at distinct sites they may also be most effective at different stages of the disease process and so may be better used sequentially. Several other compounds have been shown to prolong the incubation period of scrapie in mice [21,22], and it will be important to determine if they act at the same stages as the compounds discussed above or whether they offer additional potential sites of action. Substantial problems can be anticipated in transforming many of the currently available Reviews in Medical Virology Rev. Med. Virol. 2002; 12: 1–3. DOI: 10.1002/rmv.343