Prion-Related Diseases Medication

Updated: Oct 27, 2014
  • Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Medication Summary

All prion diseases are fatal; no effective treatment is available. Patients are currently provided symptomatic treatment. Hence, some patients with CJD who develop seizures should be administered antiepileptic drugs, while those with extrapyramidal symptoms should be administered anti-Parkinson drugs.

A number of medications have been shown in experimental systems to be effective at preventing prion propagation. These have included Congo red and its analogs, [85, 86, 87, 88] anthracyclines [89] , amphotericin B and its analogs, [90, 91, 92, 93, 94] sulfated polyanions, [95, 96, 97] and tetrapyrroles. [98, 99] Some of these have been shown to delay the incubation times of animals infected with scrapie, but these agents have limitations in terms of toxic effects and/or unfavorable pharmacokinetic properties. Of these compounds, amphotericin B failed to ameliorate CJD in a single patient. [100]

In addition, tissue culture studies have shown that acridine and phenothiazine derivatives (eg, quinacrine, chlorpromazine) can inhibit the conversion of PrPC to PrPSc. [101] These types of drugs have been used in humans for many years as antimalarial and antipsychotic drugs; however, recent reports of anecdotal use of these agents in limited numbers of patients with sporadic CJD or vCJD have so far not supported their use, [102] and animal studies have also been negative. [103, 87, 104] An extensive clinical trial (PRION-1) on this approach was initiated in the UK in 2004 (see National Prion Clinic).

Another compound that is being tested in patients is pentosan polysulphate, which seemed promising based on an animal study. [87] This compound does not cross the blood-brain barrier and has been delivered by intraventricular administration to symptomatic patients. In the only reported vCDJ case study using this approach, no obvious side effects were observed, and the clinical symptoms appeared to be slightly attenuated, although brain atrophy progressed based on CT scans. [105]

The author and their colleagues have recently designed a number of compounds that interact with the PrPSc structure and act as beta-sheet breakers, [106, 107, 108] inhibiting the conformation of PrP associated with disease. These compounds were designed by first synthesizing a large number of different PrP homologous peptides. These were then screened for inhibitory activity on the conversion of PrPC to PrPSc using an in vitro system. That synthetic peptides corresponding to PrP residues 109-141 can reproduce some of the properties of PrPSc in vitro is well known. [109, 110, 111] The author's studies determined the ability of these various candidate beta-sheet breaker peptides to inhibit amyloidlike fibril formation of PrP109-141 using a fluorometric assay based on the fluorescence emission of thioflavine T. [112, 113] This assay showed that a 13-residue peptide (iPrP13) had the greatest beta-sheet–breaking capability. Using this peptide,the author and his colleagues were able to show that the proteinase K sensitivity of extracted mouse PrPSc and of human PrPSc extracted from patients with sporadic CJD or from patients with vCJD was increased in a concentration-dependent fashion by iPrP13. [106]

The in vivo effect of iPrP13 was tested by using mouse-adapted scrapie strain 139A. Incubation time assays were performed using 3 different 10-fold dilutions of extracted 139A PrPSc, in the presence or absence of an equimolar concentration of iPrP13. At each dilution, one group of mice was injected with untreated and nonincubated PrPSc, a second group was inoculated with PrPSc that was incubated for 48 hours alone, a third group was inoculated with PrPSc and nonincubated iPrP13, and a fourth group was inoculated with PrPSc and iPrP13 incubated for 48 hours. iPrP13 induced a substantial delay in the appearance of disease. These results suggest that beta-sheet breakers may have therapeutic potential in the prionoses.

This type of therapeutic approach, in which the disease-associated abnormal protein conformation is the target, currently is under extensive investigation for the prionoses as well as for other conformational disorders, such as Alzheimer disease. [114, 115]

Other more recent approaches include chelation therapy. Copper has been implicated in prion propagation, [116] and the authors have demonstrated that a chelator, D-penicillamine, which selectively chelates copper, delays the onset of prion disease in infected mice. [117] In vitro, copper enhanced the proteinase K resistance of the prion protein, which was counteracted by co-incubation with D-penicillamine. Overall, these findings indicate that copper levels can influence the conformational state of PrP, thereby enhancing its infectivity, and this effect can be attenuated by chelator-based therapy.

An additional therapeutic approach that may be of benefit for the prion diseases is immunological. [118] A number of recent reports have shown that immunization with alpha-helix peptides is highly successful at reducing cerebral amyloid accumulation, a key neuropathologic feature in Alzheimer disease, in transgenic mouse models of that disease. [119, 120, 121, 122]

Alpha-helix peptides are normal constituents of biological fluids such as blood and CSF at low concentrations, and they are the major component of the amyloid deposits that characterize Alzheimer disease. Passive immunization studies in the Alzheimer disease model mice suggest that an antibody-mediated clearance of alpha-helix peptides is critical for a therapeutic response. [123] The authors have extended this immunological approach to prion disease and suggest that this approach can be applied to all members of the extended category of neurodegenerative conformational diseases. [124, 125, 126, 127]

Interestingly, prior work has shown that vaccination with an attenuated CJD strain can prevent expression of a more virulent strain. [128] The authors have reported that vaccination with recombinant mouse prion protein (recPrP) delays the onset of prion disease in mice. [124] Vaccination was performed both prior to peripheral prion exposure and after exposure. A delay in disease onset was observed in both groups but was more effective in animals immunized prior to exposure. The increase in the incubation period closely correlated with the anti-PrP antibody titer. The mechanism of the delay with vaccination is not clear, but the correlation of the increased incubation time with antibody titer. The authors subsequently showed that passive immunization in mice using anti-PrP antibodies prolonged the incubation times, which suggests that humoral immunity is critical for a therapeutic response. [127]

Subsequent mouse studies using much higher doses of antibodies completely prevented symptoms of prion disease. [129] Antibody administration is unlikely to be used prophylactically in large populations because of high cost but can potentially be used in humans following accidental exposure.

The authors were recently able to prevent symptoms in about 30% of infected mice by administering a Salmonella -based prion vaccine, [125] which because of low cost has the potential to be used prophylactically in livestock and perhaps also in high-risk human populations. Antibody binding to PrPC and/or PrPSc may possibly interfere with PrPSc -mediated conversion of PrPC to PrPSc and thereby delay the onset of clinical symptoms. Recent in vitro studies support this view, [130, 131] and immunization with prion peptides of 20 amino acids has been shown to reduce the levels of PrPSc in scrapie-infected mouse tumors [132] without affecting PrPC levels. Hence, epitope mapping of the anti-PrP antibodies produced by immunization may provide insights on which portions of the prion molecule are important for prion replication.

The ultimate goal of such immunological approaches is for human testing; the recent problems with the phase II clinical trial of A-beta1-42 vaccination for Alzheimer disease highlight the difficulties of translating successful therapeutic approaches from mouse models to humans (in this trial of A-beta1-42, a significant number of patients developed encephalitis as a complication). A number of potential toxic side effects of vaccine-based approaches exist in humans; further animal and in vitro experimentation is required. One source of potential toxicity is from the immunogen that is used. In the authors' Alzheimer disease vaccine development studies, the A-beta sequence was altered, making it nonfibrillogenic and nontoxic while maintaining or increasing its immunogenicity, to overcome this source of toxicity. [133, 134]

Similar types of alterations are underway to limit any potential toxicity from using the native PrP sequence as an immunogen. The authors' in vivo findings serve as a starting point for the development of vaccine-based approaches for the prion diseases and suggest that prion-based immunization is promising as a potential therapy.