Prion Disease: Chemotherapeutic Strategies

Abstract

Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with antiprion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemicalbased treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.

Anti-Prion Activity of a Panel of Aromatic Chemical Compounds: In Vitro and In Silico Approaches

“…A great number and variety of molecules have been evaluated both in vitro , and in vivo for anti-scrapie activity [8]–[14]. Many small organic compounds block PrP conversion in cell cultures infected with scrapie prion strains [8], [9], and examples of several classes of inhibitors are known to prolong the lives of infected rodents in vivo [8]–[11], [13]. However, clinical applicability of these compounds is severely limited by a lack of activity when administered after the onset of clinical signs of disease, poor bioavailability to the brain, and/or high toxicity [11]–[13], [15].…”

Comparison of the Anti-Prion Mechanism of Four Different Anti-Prion Compounds, Anti-PrP Monoclonal Antibody 44B1, Pentosan Polysulfate, Chlorpromazine, and U18666A, in Prion-Infected Mouse Neuroblastoma Cells

“…One of the major targets of the therapeutics is believed to be the inhibition of PrP Sc formation or acceleration of PrP Sc degradation, although protection of neurons from neurotoxic conditions and/or regeneration of damaged neurons are also therapeutic target [2]–[4]. To date, numerous compounds have been reported to inhibit PrP Sc formation in cells persistently infected with prions, and a few of them showed prolonged survival time in mouse models, particularly treatments that were initiated in the middle or late stages of prion infection [5]. Moreover, clinical trials of some compounds such as pentosan polysulfate (PPS), doxycycline, and quinacrine, which have been reported to inhibit PrP Sc formation in vivo and in vitro, have been conducted in patients with human prion diseases.…”

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

“…Many studies have used PrP as a therapeutic target, either blocking conversion by directly binding PrP or PrP Sc , sequestering PrP to a location where it cannot be converted, suppressing PrP expression, interfering with molecules that promote conversion, or enhancing clearance of PrP Sc (1). A major reason that these attempts have failed is that by the time symptoms are apparent, pathology is well established and cell death cascades may already be initiated; preventing further PrP Sc accumulation at this stage may be insufficient.…”