Creutzfeldt-Jakob disease: can an infectious protein be treated?

Written by Sharon Salt, Editor

Creutzfeldt-Jakob disease (CJD) is a rare, degenerative and fatal brain disorder belonging to a family of human and animal diseases, known as transmissible spongiform encephalopathies, or prion diseases [1].
It was initially believed that a transmissible agent, such as a virus, was responsible for causing the disease. However, more recently the consensus has become that prions actually transform normal proteins into infectious molecules [2]. Although a transmissible agent is responsible for CJD, it isn’t considered to be contagious in a traditional sense.

At present, four major categories of CJD have been identified (Table 1). The most common form of the disease is termed, ‘sporadic’ and is believed to be caused by the infectious prion proteins. In the UK, the number of deaths attributable to sporadic CJD has been recorded at 28, with this number steadily increasing to 131 in 2018 (Figure 1).

Symptoms of CJD closely resemble those of other forms of dementia, such as progressive loss of brain function and mobility, slurred speech, and changes in personality. Thus, it comes at no surprise that diagnosis of the disease remains a significant challenge [1,5]. Currently, the only way to confirm a diagnosis is by brain biopsy or autopsy.

In terms of treatment options for CJD, several compounds have been trialed in human studies but unfortunately, there are no effective treatments available. In this editorial, we explore some of the treatments that have been studied in humans and take a look at what the future may hold for treating this disease.

Figure 1. Number of definite and probable CJD deaths in the UK by calendar year. †As at 4 February 2019. Data taken from [4].


Which drugs have been tried and tested for CJD?
Quinacrine

Conversely, early diagnosis and participation may also be challenging given the rarity of the disease and similarity of symptoms to other forms of dementia.”

The first treatment we explore is the antimalarial compound quinacrine. In the UK, quinacrine has been tested in an open-label, patient-preference trial termed PRION-1 [6]. Within the study, 107 individuals with prion disease (45 sporadic, two iatrogenic, 18 variant and 42 inherited) were enrolled and given the choice of the drug (300 mg daily), no drug, or randomization to immediate quinacrine or deferred quinacrine. The researchers reported that quinacrine was reasonably tolerated but did not significantly affect the clinical course of prion diseases in the study [7].

Another human trial was conducted in the USA that examined whether oral quinacrine could increase survival in sporadic CJD [8]. In the study, 54 patients were randomized to quinacrine (300 mg daily) or placebo, but only 51 individuals with sporadic CJD were included in survival analyses. Unfortunately, their results indicated no significant difference between the two groups [8].

Despite a lack of success with quinacrine, these trials do provide valuable insight for future clinical trials. For instance, both trials mentioned above investigated the use of quinacrine on individuals who were in advanced stages of the disease, presenting with significant cognitive and functional impairment. This raises the question if earlier diagnosis and study participation would be more beneficial. Conversely, early diagnosis and participation may also be challenging given the rarity of the disease and similarity of symptoms to other forms of dementia.

Pentosan polysulphate

“…there would have been a limited amount of data to determine whether a clinical benefit was observed, even if the results did appear to arrest disease progression.”

A second drug candidate that has been tested is pentosan polysulphate (PPS), which is a drug primarily used as an anticoagulant in Europe [6]. In 2006, a case report was published on the ‘Unsuccessful intraventricular PPS treatment of variant CJD’, which described the case of a 39-year-old female [9]. PPS dosage was increased over 18 days from 1.1 µg/kg/day to 110 µg/kg/day and no immediate adverse effects were reported from treatment. However, at 16 months post diagnosis and 5 months after PPS treatment was commenced, the patient was reported to have died from disease progression [9].

Additionally, another paper was published that reported the case of a 22-year-old male with variant CJD who was treated 19 months after the onset of clinical symptoms, with continuous PPS (32 µg/kg/day) over a period of 31 months. Although PPS treatment appeared to be safe and well tolerated in this instance as well, it did not appear to arrest the progression of the disease [10].

Overall the authors determined that there was no definite clinical benefit that was observed with PPS. As these reports were based on case studies, there would have been a limited amount of data to determine whether a clinical benefit was observed, even if the results did appear to arrest disease progression. If that were the case, it would have perhaps warranted further investigation.

Doxycycline

“…however, it does provide valuable insight into how early treatment could increase the likelihood of a better survival outcome.”

Moving away from anticoagulants and antimalarial compounds, researchers have also trialed and tested tetracyclic antibiotics. In this particular instance, doxycycline was investigated in a Phase II, randomized, double-blind, placebo-controlled trial [11]. Patients were randomly assigned (1:1) to receive oral doxycycline (100 mg daily) or placebo from the day of randomization to death. The researchers reported that although doxycycline was well tolerated by the study participants, it did not significantly affect the disease course.

Subsequently, the results of the above trial may have unsuccessfully demonstrated doxycycline efficacy due to the stage of CJD at which patients were enrolled into the trial. Therefore, a second double-blind, randomized Phase II study was then initiated by Vargas and colleagues, who examined the therapeutic efficiency of doxycycline in early sporadic CJD [12].

Within this study, the randomized-controlled trial included seven patients from the treatment group who were compared with five patients on placebo, which revealed no significant differences in survival. Nonetheless, in their observational study, 55 patients with sporadic CJD who received doxycycline treatment were compared with historical control subjects, revealing that the treatment group displayed a significantly longer survival time [12].

This finding could be attributable to the small sample size of the trial; however, it does provide valuable insight into how early treatment could increase the likelihood of a better survival outcome. In agreeance with the authors, a much larger trial of doxycycline is required in people with the earliest stages of CJD.

Flupirtine

Another compound to add to the list is an antipsychotic drug termed, flupirtine, which has been evaluated in one clinical trial in Germany [6]. This double-blind study included 28 participants with CJD who were randomized to an oral treatment with either flupirtine (n = 13) or placebo (n = 15) [13].

To monitor disease progression, the investigators used standardized questionnaires, with the main outcome variable being the Alzheimer’s Disease Assessment Scale (ADAS-Cog). The drug was reported to have beneficial effects on the cognitive function of patients with CJD, with the flupirtine group demonstrating significantly less deterioration in the dementia tests than individuals treated with placebo. Despite the beneficial effects on cognitive function being noted, there was no increased survival benefit [13]. Although these results can be deemed as positive, further investigations are required.
Future outlook: biomarkers and emerging options for CJD
Could a skin test detect prion infections?

Although it’s been near impossible to detect CJD in the preclinical stages, a team of researchers have recently developed a skin test that could detect prion infection before symptoms appear [14]. In this study, Zou and colleagues successfully detected prions in rodent skin samples as early as 2 weeks post-infection. Could this new test replace brain biopsies to confirm a diagnosis of CJD, though? It’s still very early days, but if a prion therapy does become available in the future, then this would serve as an extremely valuable biomarker for monitoring disease progression and assessing treatment options.

PRN100

Although there is no way to determine whether PRN100 is a suitable candidate at the moment, it paves the way forward and provides hope for a potential treatment candidate for CJD.

In October 2018, it was announced that a pioneering treatment for CJD was to be given to a patient for the first time. This experimental drug, which is an artificially manufactured antibody termed PRN100, is designed to prevent abnormal prion proteins from attaching themselves to healthy proteins in the brain [15].

In prion-infected mice, PRN100 has been reported to successfully extend survival time from less than 200 days to >600 days, which is considered to be a normal lifespan. Additionally, these long-surviving mice displayed no evidence of prion infection when investigators carried out post-mortem examinations [6].

Not long after this in December 2018, investigators from University College London Hospitals (UK) confirmed that they would be giving the antibody treatment to two more patients [16]. A month later, the investigators confirmed that a fourth patient will be given the innovative CJD treatment [17]. Unfortunately, in their most recent update, the researchers announced that the third patient to have received PRN100 died. However, as the investigations conducted are still in their infancy, it is too early to determine whether this was a direct result of the treatment, or to what extent the treatment impacted their condition.

Although there is no way to determine whether PRN100 is a suitable candidate at the moment, it paves the way forward and provides hope for a potential treatment candidate for CJD.

Gene therapy

“…one of the biggest obstacles that come to mind is how the high cost of this therapy will limit its availability to patients.”

With gene therapies becoming a rapidly emerging platform for neurological disease treatment, particularly for rare diseases, it seems to be a logical approach to take for the treatment of CJD as well. In one study titled, ‘Effective gene therapy in a mouse model of prion diseases’, researchers used lentiviral gene transfer to deliver PrPQ167R virions, which possess anti-prion properties, into mice in order to analyze their efficacy in vivo. They revealed that after only two chronic injections, survival of the treated mice was extended by 30 days (20%), suggesting that this could be a promising approach for the treatment of prion diseases [18].

A second study that investigated antisense oligonucleotides to delay or prevent the onset of prion disease in mice was also carried out, with preliminary data demonstrating the development of antisense oligonucleotides that could lower prion protein (PrP) by approximately 50% in the mouse brain [19].

Earlier last year, Byron Caughey (National Institute of Allergy and Infectious Diseases, MT, USA) provided an update on this second project. In mouse studies done in his lab, antisense oligonucleotides were given in microinjections, which started before the mice were infected with prions, and the results indicated that the treated mice lived approximately 70% longer than untreated mice [19].

While gene therapy may be an up-and-coming treatment approach for CJD, one of the biggest obstacles that come to mind is how the high cost of this therapy will limit its availability to patients. This is particularly true when considering a rare disease where the incidence is approximately one in every 1 million per year worldwide [1].

Conclusion

With the number of deaths attributable to CJD on the rise, particularly in the UK (Figure 1), the search to find an effective treatment for the disease has never been more imperative. Many compounds have been trialed and tested, however, clinical trials have seen very little success.

In some instances, drugs such as doxycycline have had contradictory results when reporting on extended survival times. But are these down to the small number of participants enrolled, or does the effect of treatment depend on which stage of the disease the patient presents with?

Whilst there is no effective treatment currently available for CJD, there are a couple of promising approaches in the pipeline. Although these approaches face similar critique to previously studied candidates, such as the number of study participants involved, they’re still in the playing field for driving the pitch forward and bringing us closer to a potential treatment for CJD.

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References

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[9] Whittle IR, Knight RSG, Will RG. Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease. Acta Neurochirurgica 148(6), 677–679 (2006).

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[11] Haïk S, Marcon G, Mallet A et al. Doxycycline in Creutzfeldt-Jakob disease: a Phase II, randomized, double-blind, placebo-controlled trial. Lancet Neurol. 13(2), 150–158 (2014).

[12] Varges D, Manthey H, Heinemann U et al. Doxycycline in early CJD: a double-blinded randomized Phase II and observational study. J. Neurol. Neurosurg. Psychiatry 88, 119–125 (2017).

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[14] Wang Z, Manca M, Foutz A et al. Early preclinical detection of prions in the skin of prion-infected animals. Nat. Comm. doi:10.1038/s41467-018-08130-9 (2019).

[15] Neuro Central. Pioneering CJD treatment to be tested in patient for the first time.
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[16] University College London Hospitals. Two more UCLH patients to receive pioneering treatment for CJD.
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[17] University College London Hospitals. Fourth UCLH patient to be given innovative treatment for CJD.
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[18] Toupet K, Compan V, Crozet C et al. Effective gene therapy in a mouse model of prion diseases. PLoS ONE 3(7), e2773 (2008).

[19] CureFFI. CJD Foundation Family Conference 2018.
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Source

  1. Neuro Central