Therapeutic strategies in prion disease: current evidence, translational challenges, and emerging directions

 REVIEW article Front. Neurosci., 02 September 2026 Sec. Neurodegeneration Volume 20 - 2026 | https://doi.org/10.3389/fnins.2026.1924347

Therapeutic strategies in prion disease: current evidence, translational challenges, and emerging directions

Yixin Zhu Yixin Zhu Barry M. Bradford Barry M. Bradford Neil A. Mabbott Neil A. Mabbott * The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, United Kingdom 

Abstract Background: Prion diseases are rare, transmissible, and invariably fatal neurodegenerative disorders caused by the conformational conversion of cellular prion protein (PrPC) into its pathogenic isoform (PrPSc). Despite decades of research, no licensed disease-modifying therapies are currently available. This reflects the rapid clinical course of these disorders, the difficulty of early diagnosis, and the biological challenge of targeting a self-propagating protein misfolding process within the central nervous system.

Results: This narrative scoping review maps the current therapeutic landscape in prion disease, with emphasis on the molecular mechanisms of pathogenesis, historical and emerging treatment strategies, and other exploratory therapeutic candidates. The included literature covers PrP-lowering strategies, anti-PrP immunotherapy, downstream modulation of glial dysfunction, and broader translational barriers that continue to limit clinical development. Overall, therapeutic research has shifted from repurposed small molecules toward more mechanism-based strategies. These include PRNP-targeting strategies using antisense oligonucleotides, siRNA, and genomic editing technologies, as well as anti-PrP immunotherapy. Collectively, these strategies provide a stronger biological rationale than earlier compounds, although evidence from human trials remains limited, early-phase, or absent. In parallel, increasing evidence indicates that maladaptive glial cell activation and chronic neuroinflammation contribute substantially to disease progression and may represent additional therapeutic targets.

Conclusion: Current evidence supports increasing emphasis on integrated, mechanism-based strategies that combine suppression of prion propagation with modulation of downstream tissue injury. However, evidence of clinical efficacy in human patients is lacking. Future progress will depend on earlier diagnosis, improved translational models, and more rigorous human evaluation. 

1 Introduction

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3.5 Anti-PrP immunotherapy: preclinical and translational evidence

In parallel with substrate-lowering approaches, anti-prion immu- notherapy has emerged as a promising but technically challenging therapeutic strategy (Taschuk et al., 2015; Jones et al., 2010; Peretz et al., 2001; Féraudet et al., 2005; White et al., 2003). As shown by cell- based models, Anti-PrPC monoclonal antibodies may bind cellular prion protein, interfere with its conversion to PrPSc, or facilitate clear- ance of disease-associated PrP species (Peretz et al., 2001; Enari et al., 2001; Bender et al., 2019; Perrier et al., 2004). Animal studies provided further support for passive immunotherapy. White et al. (2003) showed that anti-PrP monoclonal antibodies delayed disease onset and prolonged incubation time in prion-exposed mice (White et al., 2003). Subsequent studies extended this rationale to additional anti- body platforms, including ICSM18, ICSM35, and other monoclonal antibodies directed against distinct epitope (Adhikari et al., 2021; Reilly et al., 2022; Klöhn et al., 2012; Ma et al., 2016; Makarava et al., 2019; Manson et al., 1994). Ohsawa et al. (2013) further demonstrated that peripheral administration of an anti-PrP monoclonal antibody prolonged survival in prion-infected mice, indicating that at least some degree of therapeutic efficacy might be achieved without direct intracerebral delivery. Nevertheless, therapeutic benefit varied sub- stantially according to antibody identity, epitope specificity, adminis- tration route, dose, and timing relative to infection. Much of the strongest preclinical efficacy was observed when treatment was initi- ated before or soon after prion exposure, whereas relevance to treat- ment of established symptomatic disease remains less certain. Contradictory findings from several preclinical studies demonstrate that anti-PrP antibodies exhibit high heterogenicity and cannot be regarded as a uniformly protective therapeutic class. Antibodies within the POM series recognize non-overlapping regions of the PrPC and differ markedly in their biological effects (Polymenidou et al., 2008; Gilch et al., 2003). Some antibodies suppress prion propagation, whereas others can induce acute neuronal injury. Antibodies targeting

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certain globular-domain epitopes, including POM1, induce acute neu- rotoxicity, and may activate neurotoxic pathways that converge with those triggered by prion infection itself (Reimann et al., 2016; Herrmann et al., 2015). ICSM18 showed a more favorable toxicity profile. Therapeutic development therefore requires careful selection of antibody epitope, affinity, valency, and mode of target engagement rather than assuming that all PrP-binding antibodies will be protective. PRN100, a humanized monoclonal antibody derived from ICSM18, is the most clinically advanced anti-PrP antibody reported to date (Mead et al., 2022). In the first-in-human treatment pro- gramme described by Mead et al. (2022), PRN100 was administered intravenously to six patients with CJD under a Special License frame- work. The study demonstrated that repeated systemic administration was feasible, that the antibody reached pharmacologically relevant concentrations in cerebrospinal fluid, and that treatment was broadly tolerated in this small cohort. These findings addressed important questions regarding delivery and short-term safety. However, all treated patients continued to deteriorate neurologically and died from their disease. Because the programme involved only six patients, lacked a randomized control group, and treated individuals with rap- idly progressive disease, it could not determine whether PRN100 pro- duced any modest effect on functional decline or survival. The study should therefore be interpreted as evidence of feasibility and CNS exposure rather than evidence of clinical efficacy.

The negative clinical course of the treated patients does not neces- sarily invalidate the underlying therapeutic principle, but it highlights several translational barriers. First, antibody penetration into the CNS remains limited relative to circulating concentrations, and CSF expo- sure may not accurately reflect uniform target engagement throughout affected brain regions (Mead et al., 2022). Second, treatment initiated after extensive synaptic dysfunction and neuronal loss may be unable to reverse established neurodegeneration, even if further PrP conver- sion is partly suppressed. Third, the possibility of target-mediated neurotoxicity narrows the therapeutic window and requires more extensive safety assessment than would be necessary for antibodies directed against an inert extracellular target. Finally, no validated pharmacodynamic marker has yet shown that antibody exposure in patients results in reduced prion seeding activity or meaningful inhi- bition of PrP conversion (Mead et al., 2022).

A possible role for anti-PrP antibodies in presymptomatic or post- exposure settings has been proposed because several animal studies achieved their greatest benefit when treatment was initiated early (White et al., 2003; Adhikari et al., 2021; Reilly et al., 2022; Klöhn et al., 2012; Ohsawa et al., 2013). In principle, passive immunotherapy administered shortly after accidental or iatrogenic exposure might reduce peripheral prion amplification or delay neuroinvasion (Klyubin et al., 2014; Masone et al., 2025). However, this application remains untested in humans, and the available evidence does not establish that PRN100 can neutralize prions after exposure, prevent CNS invasion, or alter long-term disease risk. Practical limitations would also include identifying a credible exposure event, defining an effective treatment window, achieving adequate distribution to peripheral lymphoreticu- lar tissues and the nervous system, and balancing uncertain benefit against repeated antibody administration. Post-exposure prophylaxis should therefore be presented as a preclinical research hypothesis rather than a clinically realistic current indication.

Overall, anti-PrP monoclonal antibodies have strong mechanistic support and reproducible evidence of anti-prion activity in cellular and selected animal models. However, their translational potential is constrained by variable efficacy across antibodies, dependence on early treatment, limited CNS penetration, and epitope-specific neuro- toxicity. PRN100 represents an important translational milestone because it demonstrated that systemic anti-PrP antibody administra- tion and measurable CNS exposure are feasible in patients.

Nevertheless, no survival or functional benefit has yet been estab- lished, and future development will require antibodies with carefully validated epitope specificity, favorable neurotoxicity profiles, improved CNS delivery, and biomarkers capable of distinguishing target engage- ment from genuine disease modification.

Taken together, PRNP- and PrP-directed therapies intervene at several levels of the pathogenic process, including suppression of PRNP transcription, depletion of PrPC substrate, durable genomic dis- ruption, inhibition of PrPSc conversion, and antibody-mediated neu- tralization of PrP species (Table 2). Their evidence bases and translational readiness differ substantially. ASOs currently have the most advanced clinical development pathway, siRNA remains in early human evaluation, genome editing is restricted to preclinical proof- of-concept studies, and anti-PrP antibodies have demonstrated clini- cal feasibility without established efficacy.

3.6 Glial cells as novel cellular therapeutic targets in prion disease

3.6.1 Therapeutic modulation of microglia: opportunities and translational limitations

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4 Discussion and limitations This review highlights a major transition in prion therapeutic development from screening of repurposed compounds towards mechanism-based approaches targeting fundamental processes involved in disease progression. While earlier compounds demonstrated anti-prion activity in experimental systems, their limited clinical success highlights the substantial challenges associated with modifying a rapidly progressive neurodegenerative disease driven by self-propagating protein misfolding. These challenges include delayed diagnosis, limited therapeutic windows, incomplete CNS target engagement, and the difficulty of translating findings from experimental models into human disease. The current therapeutic landscape suggests that approaches targeting the upstream mechanisms of prion propagation, particularly reduction of PrP availability, provide the strongest biological rationale for disease modification. However, clinical translation remains incomplete, and no intervention has yet demonstrated clear efficacy in human prion disease. Other approaches, including direct PrP immunotherapy and modulation of downstream pathological processes such as neuroinflammation and glial dysfunction, may provide complementary therapeutic opportunities but remain limited by uncertainties regarding efficacy, safety, and optimal timing of intervention. Importantly, emerging strategies such as genome editing, protective PrP variants, and other approaches should currently be regarded as exploratory concepts requiring further validation rather than established therapeutic candidates. The lack of clinical success to date also reflects broader challenges in prion therapeutic development rather than failure of individual therapeutic concepts alone. Human prion diseases are rare, rapidly progressive disorders, making clinical trial recruitment and evaluation of therapeutic benefit particularly challenging. Furthermore, most patients are diagnosed after substantial neuronal loss has occurred, when suppressing further prion propagation may be insufficient to restore neurological function. Therefore, future therapeutic development will depend not only on identifying effective molecular targets, but also on improving early diagnosis, developing reliable biomarkers for patient stratification and treatment monitoring, and establishing translational models that better predict human outcomes.

This review has several limitations. As a narrative scoping review, it does not provide a systematic assessment of all available evidence or formal risk-of-bias analysis. Furthermore, the therapeutic literature in prion disease spans diverse experimental systems, from cell-based studies to early clinical trials, which differ substantially in their ability to predict human efficacy. Findings derived from other neurodegenerative disease models, particularly for glial-directed or regenerative approaches, should therefore be interpreted cautiously due to differences in disease mechanisms and therapeutic requirements. Overall, future progress will depend on integrating biologically rational interventions with improved early diagnosis, validated biomarkers, and rigorous clinical evaluation. While no disease-modifying therapy is currently available, recent advances in PrP-targeting strategies provide a stronger foundation for translational development than previous approaches.

5 Concluding remarks Prion disease remains one of the most therapeutically challenging neurodegenerative disorders, owing to its rapid clinical progression, diagnostic limitations, and the biological difficulty of targeting a self-propagating protein misfolding process within the central nervous system. Current evidence suggests that the most rational disease-modifying strategies are those that either reduce the availability of PrPC or interfere with its pathogenic conversion, while downstream approaches targeting proteostatic dysfunction, neuroinflammation, and glial maladaptation may offer complementary benefit. Overall, the field is moving towards more mechanism-based and combinatorial therapeutic models, but substantial translational work remains necessary before these approaches can be considered clinically effective in human prion disease.

Statements Author contributions YZ: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. BB: Conceptualization, Methodology, Project administration, Supervision, Writing – review & editing. NM: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing.

Funding The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Institute Strategic Programme Grant funding from the Biotechnology and Biological Sciences Research Council (BBS/E/RL/230002B). The open access publication of this manuscript was supported by the UKRI Open Access Fund.

Acknowledgments For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any author accepted manuscript version arising from this submission.

Conflict of interest The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author NM declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Generative AI statement The author(s) declared that Generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes 1.^https://pubmed.ncbi.nlm.nih.gov/

2.^https://webofscience.zendesk.com/hc/en-us

3.^https://scholar.google.com/

References

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2026.1924347/full

Prion protein monoclonal antibody Prion100 2026 update

Highlights from the MRC Prion Unit at UCL and National Prion Clinic Open Day 14th April 2026

Dear friends,

We were very pleased to welcome patients, relatives, at-risk family members, supporters, government and other colleagues to the MRC Prion Unit at UCL and National Prion Clinic Open Day 2026. For those who were not able to join us, we wanted to share a summary of the day and some of the main messages from each speaker, along with highlights from the afternoon discussion groups and laboratory tours.

Peter Mills, John Camidge and Charlotte Saigne from the Cure CJD Campaign, pictured with Professor John Collinge (second from left), at the Open Day.

Welcome and introduction

Rachel Williams opened the day on behalf of the National Prion Clinic. She introduced the clinic team, welcomed guests, and set out the programme, which combined research updates, discussion, and practical information about support and involvement. The aim was not only to share progress, but also to hear from patients, families, and supporters about what matters most to them.

Lead Nurse Rachel Williams opened the day by welcoming visitors and introducing the programme.

Professor John Collinge: overview of the field and treatment development

Professor John Collinge gave the opening scientific talk. He began by explaining, in accessible terms, what prion diseases are and why they are so unusual. Prion diseases arise when a normal protein in the brain changes shape and begins to misfold. That misfolded protein can then encourage other copies of the same protein to misfold in turn. Over time this process damages the brain. He also explained the three broad ways prion disease can arise in humans:

• sporadically, with no known trigger;

• through inherited changes in the prion protein gene;

• or, much more rarely, through acquired exposure.

MRC Prion Unit at UCL:

He then described the work of the MRC Prion Unit at UCL as a whole, from genetics and basic laboratory science through to diagnostics, biomarker research, and treatment development.

A major focus of his talk was PRN100, the antibody treatment developed at the Unit to target the normal prion protein and block the disease process. The central message was that the first clinical use of PRN100 showed that the antibody could be given safely and could reach the brain. Although the first treated patients had advanced disease, and the study was not designed as a formal efficacy trial, the results were encouraging enough to support the case for a more definitive early-stage trial.

Professor Collinge was frank that the next step will require substantial funding, but he also made clear that this is now a real translational programme rather than a distant aspiration.

Why does prion research matter?:

He also spoke about why prion research matters more widely. Understanding how proteins misfold, spread, and damage the brain may help not only in prion disease but also in other neurodegenerative disorders.

He touched on work from the unit suggesting that, in very rare historical medical circumstances, proteins involved in Alzheimer’s disease may also be capable of behaving in a prion-like way. This does not mean Alzheimer’s disease is contagious in ordinary life.

The mechanisms first worked out in prion disease may have much wider relevance across neurology.

Dr Mok: biomarkers and prediction before symptoms

Dr Mok then gave an important update on biomarkers in inherited prion disease.

A biomarker is a measurable signal in the body that can help us understand whether a disease process is active, sometimes before clear symptoms appear. In prion disease, one of the most promising tools is a highly sensitive spinal fluid test that can detect abnormal prion seeding activity. Dr Mok described evidence that in people carrying the E200K mutation, this test can become positive years before symptoms begin.

That matters because it suggests there may be a window in which treatment could be given earlier, before major damage is done.

This was one of the most striking messages of the day. Dr Mok explained that the work is still developing and that it currently applies most clearly to one inherited form of disease rather than all genetic prion diseases. Even so, it opens the possibility of much more accurate risk prediction for some individuals and, in time, better-designed prevention studies. He was careful to acknowledge that this also raises difficult personal and ethical questions. Not everyone would want this kind of information, and any future use would need proper counselling and support.

Dr Leah Holm-Mercer: early changes in brain activity

Dr Leah Holm-Mercer then spoke about how brain activity may change in the early stages of prion disease, before diagnosis is made. She described work using EEG and MEG, two non-invasive ways of measuring the brain’s electrical and magnetic activity. Her central point was that subtle changes in brain function may be detectable earlier than obvious clinical decline. If so, these measures could help researchers track very early disease and judge whether treatments are working at a stage when intervention may have the best chance of success.

This work is still at an early stage, but it reflects an important shift in the field.

Future trials are likely to depend not only on whether a treatment is safe, but also on whether we can measure meaningful changes early enough and accurately enough. Dr Leah’s presentation showed how this kind of research may become part of that answer.

Dr Leah Holm-Mercer demonstrating the MEG Scanner at NHNN

Cure CJD campaign https://curecjd.org/

We then heard from Cure CJD, the fundraising campaign established by families and supporters to help drive treatment research forward. The speakers described the campaign’s purpose, its volunteer-led nature, and the determination to help bridge the gap between promising science and the large sums needed to run formal clinical trials. A key next step will be a Parliamentary event in July, intended to raise awareness among decision-makers, potential donors, and the wider public.

The message was simple: progress is being made, but it will need sustained public and political support to move faster.

John Camidge then showed a personal and moving account of a family’s experience of inherited prion disease and why they became involved in fundraising. The presenter spoke with honesty about predictive testing, family burden, and the long shadow these diseases can cast across generations. John gave practical encouragement to anyone who might want to help, whether through fundraising events, sharing stories, or simply helping to raise awareness. His talk was a reminder that behind every research programme are families living with uncertainty, grief, and hope. Visit for more information. CJD Support Network https://cjdsupport.co.uk/

We also heard from the CJD Support Network. Catherine Dougherty’s talk focused on the practical and emotional support they provide for families, as well as their role in supporting smaller research and service projects.

She highlighted recent grants, including work on artificial intelligence in diagnosis and a project led by a nurse on supporting young people affected by prion disease in their families.

She also shared details of upcoming events, including fundraising activities and the annual family meeting (12th September 2026 - registration form link: https://forms.office.com/r/kwZXs3LeJW) which remains an important opportunity for people affected by prion disease to meet others who understand the experience.

Catherine from the CJD Support Network spoke about support for families affected by prion disease, community events, and current initiatives.

Afternoon discussion groups

3 discussion groups were run in the afternoon:

• Patient and Public Involvement and Engagement group (PPIE): Rachel Williams

• Biomarkers & Risk Prediction: Dr Mok

• Treatments for CJD: Professor Simon Mead

Patient and Public Involvement and Engagement group (PPIE): Rachel Williams

Rachel Williams, Lead Nurse at the National Prion Clinic, led an afternoon discussion on the development of a National Prion Clinic Patient and Public Involvement and Engagement group.

This was well attended and explored whether such a group would be valuable, and what its role should be.

Discussion included how a PPIE group could help shape information and resources for patients, carers, and families, contribute to the design of patient-facing materials, bring lived experience to the challenges of diagnosis in a rare disease, and help inform future clinical research projects.

Those interested in joining left their contact details and will be invited to the next stage of planning.

Anyone who was unable to attend the Open Day but would be interested in the group is welcome to contact Rachel Williams at rachel.williams36@nhs.net

Biomarkers & Risk Prediction: Dr Mok

Dr Mok led a discussion group on the significance of seed amplification assay (RT-QuIC) positivity before clinical onset in E200K mutation carriers. This built on his earlier talk and allowed for more detailed discussion of what these findings might mean in practice, both for research and for future risk prediction.

The conversation also touched on the ethical and personal questions raised by this work, including how such information might be offered and supported if it becomes clinically useful.

Treatments for CJD: Professor Simon Mead

Professor Mead led a wider discussion on treatments for CJD, covering both PRN100 and other approaches under academic and commercial development.

This gave attendees the chance to ask more openly about the treatment landscape, what has been learnt so far, and where the main opportunities and obstacles now lie.

It was a useful forum for discussing both hope and realism in a field where progress is still difficult, but increasingly tangible.

Laboratory tours and demonstrations Research Technician Dr Aline Marinho demonstrated living brain cells growing in a dish, giving visitors a glimpse of laboratory methods used in the unit’s research.

PhD student Diego Caron presented his work on Alzheimer’s amyloid fibrils, including the use of transmission electron microscopy to study their structure.

During lunch and the afternoon, many visitors also took part in tours of the unit, led by students and senior staff.

These included demonstrations of the scrapie cell assay, fluorescent cell imaging, bio secure laboratory facilities, and microscopy platforms used in the unit’s research.

The tours were an important part of the day, giving visitors a direct sense of the scientific environment, the methods being used, and the people carrying the work forward.

Facility Manager George Thirlway demonstrated the automated robotic system used to run prion infectivity assays.

Visitors also saw cell lines used by Senior Technician Nunu Arora to create a human cell model of CJD.

Closing reflections

Families raised important issues about national services, surveillance, inherited risk, research, and how best to maintain momentum. There was a strong sense that while the challenges remain considerable, there is now clearer scientific direction than there was even a few years ago. Better biomarkers, stronger trial designs, and the experience gained from PRN100 all point towards a more realistic path to treatment studies.

Above all, the day was a reminder that none of this work happens without patients, families, and supporters. We are grateful to everyone who attended, everyone who has taken part in research, and everyone who continues to support the clinic, the unit, and the wider prion disease community.

With best wishes,

MRC Prion Unit at UCL / National Prion Clinic

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VOLUME 21, ISSUE 4, P342-354, APRIL 01, 2022

Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Prof Simon Mead, FRCP Azadeh Khalili-Shirazi, PhD Caroline Potter, PhD Tzehow Mok, MRCP Akin Nihat, MRCP Harpreet Hyare, FRCR et al.

Open Access Published: April, 2022 DOI: https://doi.org/10.1016/S1474-4422(22)00082-5

Summary

Background

Human prion diseases, including Creutzfeldt–Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence.

Methods

We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80–120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls.

Findings

We treated six patients (two men; four women) with CJD for 7–260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22–70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66–182 nM).

Interpretation

Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure.

Funding

The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.

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Discussion

We report our experience of the first-in-human treatment of six patients with CJD with PRN100. We show that PRN100 was safe and able to access the brain (CSF data in four patients and autopsy data in one patient) in target concentrations after intravenous dosing. Limited brain autopsy evidence from two patients showed that PRN100 treatment did not induce neurotoxicity and suggests that PRN100 might help to clear disease-related PrP from the brain. At this stage, the number of treated patients is too small to determine whether PRN100 altered the course of the disease. Based on these safety data and demonstration of brain accessibility to PRN100 following intravenous administration, a larger study, ideally at the earliest possible intervention, is now warranted.

All prion diseases are relentlessly progressive, invariably fatal conditions. However, our understanding of their requirement for PrPC for pathogenesis and unequivocal preclinical validation10, 12, 13 of the effect of targeting PrPC provide a strong expectation that passive immunotherapy with anti-PrPC monoclonal antibodies should be an effective therapeutic strategy, assuming adequate concentrations reach brain tissue without dose-limiting toxicity and that treatment is initiated before major neuronal loss and irreversible secondary neurodegenerative processes are underway. Such a treatment strategy is expected to be particularly promising as secondary prophylaxis in asymptomatic individuals known to be infected with prions or harbouring a pathogenic PRNP mutation. By targeting the obligate substrate for prion propagation and neurotoxicity, rather than prions themselves, the treatment should also be effective against all prion strains and avoid the development of drug resistance by strain adaptation and selection.34

On this firm scientific foundation, we have treated six patients with CJD with PRN100 under a Specials Licence, proceeding with great caution and independent oversight. The nature of the recruitment process for this first-in-human treatment programme meant that most patients were rapidly progressing and at the mid-stages of the disease at onset of therapy. In addition, our cautious intravenous dose-escalation protocol meant that it took a mean of 47 days to reach the target CSF concentration of 50 nM and clinically significant further neurological decline occurred during this period (for context, in the NPMC study [544 individuals with sporadic CJD], median survival from enrolment was 25 days (Q1–Q3 10–97).27 Our interpretations are necessarily limited by the small number of patients who could be treated with our single available batch of drug product, their rapid clinical progression and well established neurodegeneration at the outset of treatment, and the fact that we evaluated an NHS treatment and did not do a clinical trial with prespecified outcomes, analyses, and research biomarkers. This approach meant that clear evidence of efficacy could be concluded only if one or more patients ceased to decline neurologically or showed sustained improvement on treatment, an outcome we have not seen in our natural history study.25

Encouragingly, intravenous administration did reach our target CSF drug concentration of 50 nM in four patients and direct intracerebroventricular infusion was unnecessary. Indeed, CSF analysis indicated that PRN100 itself might have resulted in increased permeability of the blood–brain barrier, compared with baseline and controls, perhaps via interaction with PrPC on the surface of endothelial cells,35 facilitating its own entry. Most importantly, we saw no clinical evidence of toxicity and there was no evidence of cytotoxicity related to therapy in the two patients in whom autopsy examination was done. Intravenous infusion of PRN100 was well tolerated and there were no acute or chronic adverse events for up to 8 months of treatment.

Although disease progression was not halted or reversed in any patient, MRC Prion Disease Rating Scale scores did appear to stabilise in three patients for periods when CSF drug concentrations reached the target concentration, but the small number of patients precluded meaningful statistical analysis. However, neuropathological examination of patient 2 provided strong evidence of target engagement and drug effect, with striking attenuation of abnormal PrP immunoreactivity in the parietal cortex and occipital cortex, markedly altered distribution of disease-related PrP in subventricular areas, and PrP cerebral amyloid angiopathy, which was not seen in untreated patients. We note that amyloid β cerebral amyloid angiopathy has been observed as a consequence of amyloid β monoclonal antibody therapy, but we did not detect amyloid-related imaging abnormalities in any patient. The second patient on whom autopsy was done only received a single dose of 80 mg/kg but also showed altered PrP labelling in periventricular regions. Compared with untreated historical controls, concentrations of tissue-bound drug estimated in post-mortem brain tissue were similar to those in CSF, well in excess of concentrations shown to cure cells of prion infection.

We are therefore encouraged by these findings, which, taken together, suggest that intravenous administration of PRN100 treatment is safe and can attain, and sustain in the long term, brain tissue concentrations in the range expected to be therapeutically active without detectable toxicity. It will be important to now evaluate PRN100 in a regulated phase 2 study in which we would seek to enrol patients at the earliest clinical stages and perform much more rapid dose escalation to achieve target CSF drug concentrations within 48–72 h. Modelling studies based on the NPMC dataset with genetic stratification by PRNP codon 129 genotype estimate that a suitably powered trial can be conducted with 50 patients.27 The availability of this large natural history dataset of a rare disease allows innovative trial designs to assess efficacy with minimal or no randomisation to placebo, which is understandably challenging for this patient population to accept.4

Subject to satisfactory safety data, further studies to evaluate PRN100 for secondary prophylaxis to prevent the clinical onset of disease could be undertaken in carriers of PRNP mutations and those exposed to prions via medical or surgical procedures or laboratory incidents, which includes a large number of individuals treated with human cadaveric growth hormone potentially contaminated by prions (around 1800 people in the UK; around 5000 people in the USA). Possible blood biomarkers of proximity to clinical onset in people at risk could be important components of preventive studies.26 Dietary exposure to prions resulted in the historical epidemic of kuru, transmitted by ingestion of human tissues at mortuary feasts in Papua New Guinea, and variant CJD from exposure to bovine spongiform encephalopathy prions in the UK and some other countries. Although variant CJD is now very rare, screening of anonymised archived tissue has suggested that around one in 2000 people in the UK population could be silently infected following exposure to bovine spongiform encephalopathy in the 1980s and 1990s.36 Variant CJD prion infection has also been iatrogenically transmitted by blood transfusion or blood products and several thousand UK individuals have been notified that they are at risk of developing prion disease as a result of such exposure.

In addition to meeting the unmet clinical need to treat and prevent prion disease, it is anticipated that much will be learned in the course of these future clinical studies about the capacity for cognitive and neurological recovery upon halting a neurodegenerative process in humans. Such knowledge could be extremely valuable in the development and evaluation of therapies for the more common dementias. Furthermore, a growing body of data supports a role for PrPC in Alzheimer's disease in its binding of synaptotoxic amyloid β assemblies.37 The interaction between PrPC and synaptotoxic amyloid β assemblies can be efficiently blocked by PRN100, suggesting a possible future role for anti-PrP antibodies in treating Alzheimer's disease38 and, possibly, other common neurodegenerative diseases.39

Contributors

JC led the development of PRN100 with SM, AK-S, CP, NM, NE, PH, and MW. Patient assessment and treatment and review of investigations was done by JC, SM, PR, TM, AN, and HH. PRN100 assays and other laboratory investigations were designed, conducted, or designed and conducted by AK-S, SC, CS, TC, and LD. Neuropathology was done by ZJ, JL, and SB. VL and BW provided clinical advice and coordinated and liaised with the Oversight Committee. The underlying data have been verified by JC, SM, HH, AK-S, and SB. The manuscript was drafted by JC and SM, with contributions from all authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

snip...see full text;

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(22)00082-5/fulltext

https://www.thelancet.com/action/showPdf?pii=S1474-4422%2822%2900082-5

World-first CJD treatment shows promising early results 17 March 2022

A world-first treatment for Creutzfeldt-Jakob disease (CJD), developed by scientists at the Medical Research Council (MRC) Prion Unit at UCL, has shown “very encouraging” early results following its use in six patients at University College London Hospitals (UCLH) NHS Foundation.

CJD is a rare but devastating disease that causes brain damage and for which there is currently no licensed treatment. It is always fatal and most patients sadly die within a few months of diagnosis.

Researchers at the MRC Prion Unit at UCL have developed a monoclonal antibody, called PRN100, which was given to six UCLH patients with CJD between October 2018 and July 2019.

The results, published in the Lancet Neurology, show the treatment is safe and able to access the brain. In three patients, disease progression appeared to stabilise when dosing levels were in target range.

Given the small number of patients treated, researchers say the findings should be regarded as preliminary and further studies are needed to draw more comprehensive conclusions.

None of the six patients experienced side effects while receiving the treatment but all sadly died as a result of their condition.

Professor John Collinge, Director of the MRC Prion Unit at UCL and UCLH consultant neurologist, who led the development of the PRN100 treatment, said: “Drugs used to treat other diseases have been tried experimentally in treating CJD in the past but none has had an impact on disease progression or mortality.

“This is the first time in the world a drug specifically designed to treat CJD has been used in humans and the results are very encouraging.

“While the number of patients we treated was too small to determine whether the drug altered the course of the disease, this is nevertheless an important step forward in targeting prion infections.

“It has been a huge challenge to reach this milestone and we still have a long way to go but we have learned a great deal and these results now justify developing a formal clinical trial in a larger number of patients.”

Looking further into the future, Professor Collinge added: “We hope the drug may also have the potential to prevent the onset of symptoms in people at risk of prion disease due to genetic mutations or accidental prion exposure and may contribute to the development of therapies for more common dementias, such as Alzheimer’s disease.”

In a comment piece published alongside the results in the Lancet Neurology, Professor Inga Zerr, from the Department of Neurology at Georg-August University of Gottingen, Germany, also called for further studies in this area.

“These outcomes are very encouraging and long awaited but, in light of the limitations, such as the small number of patients included and the use of historical controls, these results must be considered preliminary,” she said.

UCLH provided the PRN100 drug to patients under a “Specials” exemption, rather than a regulated clinical trial. A “Specials” exemption permits a healthcare professional to treat an individual patient with an unlicensed drug when their special clinical needs cannot be met by a licensed product on the market.

Three of the six patients were able to consent to receiving the PRN100 antibody themselves. The other three did not have the capacity to consent, so with the support of their families, UCLH sought the opinion of a judge in the Court of Protection in order to proceed.

UCLH created an oversight group, independent of the MRC Prion Unit at UCL and treating clinicians, to consider the numerous and complex clinical, safety, legal and ethical issues arising from the potential use of this unlicensed treatment. The group comprised world-leading experts from a range of disciplines and met regularly with lawyers and patient advocates from the Cure CJD Campaign.

Professor Bryan Williams, director of the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre (BRC), said: “UCLH is a bold healthcare institution which, along with its academic partner UCL, is always seeking to push the frontiers of medicine and science to deliver innovative treatments to patients.

“Creutzfeldt-Jakob disease (CJD) is a rare and cruel disease which rapidly destroys the brain and for which there is currently no cure or licensed treatment. It was extremely important to us to find a way through the many challenges arising from the potential use of this novel treatment in order to offer it to a small group of patients.

“We are encouraged by these results which demonstrate the treatment is safe and there is some signal of benefit. The hope is that this could pave the way for new treatments for other neurodegenerative diseases.”

Patient story

Carole Kiralyfi was one of the six patients to receive the PRN100 antibody.

Her husband, Laszlo, said a fall during a game of tennis in January 2019 was one of the first signs that something was not right with Carole, who was 70 years old at the time. Her vision then began to deteriorate and she had difficulties managing everyday tasks.

When Carole was diagnosed with sporadic CJD in March 2019, Laszlo said the whole family was “absolutely devastated”.

“It was such a shock, everything happened so quickly. Carole had always been so healthy and active – I had always thought she would outlive me.”

With Laszlo’s support, Carole decided to receive the PRN100 drug after being thoroughly assessed by neurologists at UCLH’s National Prion Clinic.

“Carole came to terms with her diagnosis a lot better than we (her family) did – she was not afraid. The drug was our only option so we decided to go ahead.”

Carole sadly died of her condition in April 2019 before the target level of PRN100 was achieved but Laszlo takes comfort in the fact that she may have contributed to the development of a potential treatment of the future.

“Obviously, I wish there could have been a treatment for Carole but if we are one step closer to achieving that now, it means her death was not in vain.

“The team that looked after her was so caring and compassionate – they have dedicated their lives to finding a cure for this terrible disease so I want this for them too.

“CJD may be rare but it is devastating and that is why it is so important there is more research in this area.”

Paying tribute to his wife of 28 years, Laszlo, who is now 74, added: “She was an extraordinary person with a big heart; a wonderful wife and fantastic mother. She was very popular and had many friends – when she walked into a room it lit up and when she left the light remained. She will remain forever in our hearts.”

Links

Research paper published in Lancet Neurology Professor John Collinge MRC Prion Unit at UCL UCLH Medical Research Council Image

'Medical drip with patient in the hospital', credit: Kwangmoozaa on iStock Media contact

Henry Killworth

Tel: +44 (0) 7881 833274

E: h.killworth [at] ucl.ac.uk

https://www.ucl.ac.uk/news/2022/mar/world-first-cjd-treatment-shows-promising-early-results

MANY THANKS to the Lancet Journal for open access and especially to all the Scientist working to find a cure for CJD TSE PrP...terry

https://prionpps.blogspot.com/2022/03/prion-protein-monoclonal-antibody.html

terry