RARE DISEASE
Sporadic Creutzfeldt-Jakob disease
Sporadic Creutzfeldt-Jakob disease
Sporadic Creutzfeldt-Jakob disease
Synonyms: Sporadic CJD
Synonyms: Sporadic CJD
Synonyms: Sporadic CJD
Drug discovery
2
drugs
With orphan designations
Overview
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive, invariably fatal prion disorder characterized by dementia, myoclonus, visual/cerebellar disturbances, and akinetic mutism. Diagnosis relies on clinical criteria, MRI brain patterns (cortical/CSF biomarkers (14-3-3, RT-QuIC), and exclusion of mimics. Median survival is 4-8 months [1][9][13][14].
Burden
Therapies
Symptomatic management: Benzodiazepines for myoclonus, opioids for pain, antidepressants for mood [11][17]
Experimental approaches: Anti-prion monoclonal antibodies (PRN100), RNA interference, and neural precursor cell therapy show preclinical promise [3][7][19]
Clinical trials: Limited success with pentosan polysulfate/doxycycline; ASO-based gene suppression in development [7][19]
Categories: rare neurological diseases
Research Papers
319 drug discovery papers about Sporadic Creutzfeldt-Jakob disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
319 drug discovery papers about Sporadic Creutzfeldt-Jakob disease, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
vaccines
2023-02-11 | Vaccines for prion diseases: a realistic goal?
Abstract Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP C ) into the pathological PrP Sc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP C and PrP Sc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP C -directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
2014-09-30 | Prospects for safe and effective vaccines against prion diseases
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.
2013-10-20 | Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy
Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
2012-03-01 | Could immunomodulation be used to prevent prion diseases?
All prion diseases are currently without effective treatment and are universally fatal. The underlying pathogenesis of prion diseases (prionoses) is related to an autocatalytic conformational conversion of PrPC (C for cellular) to a pathological and infectious conformer known as PrPSc (Sc for scrapie) or PrPRes (Res for proteinase K resistant). The past experience with variant Creutzfeldt–Jakob disease, which originated from bovine spongiform encephalopathy, as well as the ongoing epidemic of chronic wasting disease has highlighted the necessity for effective prophylactic and/or therapeutic approaches. Human prionoses are most commonly sporadic, and hence therapy is primarily directed to stop progression; however, in animals the majority of prionoses are infectious and, as a result, the emphasis is on prevention of transmission. These infectious prionoses are most commonly acquired via the alimentary tract as a major portal of infectious agent entry, making mucosal immunization a potentially attractive method to produce a local immune response that can partially or completely prevent prion entry across the gut barrier, while at the same time producing a modulated systemic immunity that is unlikely to be associated with toxicity. A critical factor in any immunomodulatory methodology that targets a self-antigen is the need to delicately balance an effective humoral immune response with potential autoimmune inflammatory toxicity. The ongoing epidemic of chronic wasting disease affecting the USA and Korea, with the potential to spread to human populations, highlights the need for such immunomodulatory approaches.
2010-11-24 | Immunomodulation for prion and prion-related diseases
Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformational change of a normal self protein called cellular prion protein to a pathological and infectious conformer known as scrapie prion protein (PrPSc). Currently, all prion diseases lack effective treatment and are universally fatal. Past experiences with bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease mainly in Europe, as well as the current epidemic of chronic wasting disease in North America, have highlighted the need to develop prophylactic and/or therapeutic approaches. In Alzheimer’s disease that, like prion disease, is a conformational neurodegenerative disorder, both passive and active immunization has been shown to be highly effective in model animals at preventing disease and cognitive deficits, with emerging data from human trials suggesting that this approach is able to reduce amyloid-related pathology. However, any immunomodulatory approach aimed at a self-antigen has to finely balance an effective humoral immune response with potential autoimmune toxicity. The prion diseases most commonly acquired by infection typically have the alimentary tract as a portal of infectious agent entry. This makes mucosal immunization a potentially attractive method to produce a local immune response that partially or completely prevents prion entry across the gut barrier, while at the same time producing modulated systemic immunity that is unlikely to be associated with toxicity. Our results using an attenuated Salmonella vaccine strain expressing the prion protein showed that mucosal vaccination can protect against prion infection from a peripheral source, suggesting the feasibility of this approach. It is also possible to develop active and/or passive immunomodulatory approaches that more specifically target PrPSc or target the shared pathological conformer found in numerous conformational disorders. Such approaches could have a significant impact on many of the common age-associated dementias.
proteins
2025-04-30 | Abnormal Expression of Proteolytic Stress-Related Proteins and Protective Effect of Fibrinolytic Enzymes in Prion Diseases.
Prion diseases are fatal, irreversible, and infectious neurodegenerative diseases caused by proteinase K-resistant prion protein (PrPSc). Against PrPSc, several endogenous proteases involved in cellular degradation mechanisms can be activated to remove PrPSc. However, since PrPSc shows proteinase K resistance, we presumed that undegradable PrPSc induces positive feedback on the overactivation of the cellular degradation mechanisms and is correlated with proteolytic stress and exacerbation of the progression of prion diseases. We investigated the expression pattern of proteolytic stress-related proteins in the brains of ME7 scrapie-infected mice at 7 months postinfection and sporadic Creutzfeldt-Jakob disease (CJD) patients using western blotting and immunohistochemistry (IHC). In addition, we analyzed the 3D structure and binding complexes of prion protein (PrP) with nattokinase and lumbrokinase using in silico programs, including SWISS-MODEL and HawkDock. To fundamentally reduce proteolytic stress by the degradation of PrPSc, we performed an in vitro evaluation of the PrPSc degradation abilities of fibrinolytic enzymes, including nattokinase and lumbrokinase. Furthermore, we assessed the protective effects of nattokinase and lumbrokinase in ME7 scrapie-infected mice. We observed an abnormal accumulation of proteolytic stress-related proteins, including CD10, cathepsin B, cathepsin D, and matrix metalloproteinase 9 (MMP9), in the brains of ME7 scrapie-infected mice and sporadic CJD patients. In addition, we identified that nattokinase and lumbrokinase can stably bind to PrP. Furthermore, we identified significant in vitro degradation of PrPSc derived from ME7 scrapie-infected mice and sporadic CJD patients by nattokinase and lumbrokinase. Last, we found in vivo protective effects of nattokinase and lumbrokinase against prion disease in ME7 scrapie-infected mice. To the best of our knowledge, this is the first report on the identification of proteolytic stress-related novel potential biomarkers and the therapeutic potential of nattokinase and lumbrokinase for prion diseases.
2023-08-01 | Different tau fibril types reduce prion level in chronically and de novo infected cells
Neurodegenerative diseases are often characterized by the codeposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An example is represented by prion diseases, where the classical deposition of the aberrant conformational isoform of the prion protein (PrPSc) can be associated with tau insoluble species, which are usually involved in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion diseases is still a matter of debate. Recently, the cellular form of the prion protein, PrPC, has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau, and α-synuclein has been reported, and it has been linked to several neurotoxic behaviors exerted by these proteins. We have previously shown that the treatment of chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels. In this work, we further explored this mechanism by using another tau construct that includes the sequence that forms the core of Alzheimer's disease tau filaments in vivo to obtain a distinct fibril type. Despite a difference of six amino acids, these two constructs form fibrils characterized by distinct biochemical and biological features. However, their effects on PrPSc reduction were comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the pathological conversion event. Our results suggest PrPC as receptor for different types of tau fibrils and point out a role of tau amyloid fibrils in preventing the pathological PrPC to PrPSc conformational change.
2022-07-25 | Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation
Abstract Prion diseases are progressive neurodegenerative disorders with no effective therapeutics. A central event leading to the pathology in the diseases is the conversion of PrP C into PrP Sc and its accumulation in the central nervous system. Previous studies demonstrated that PrP C , recombinant PrP (rPrP) and PrP peptides can inhibit the formation of PrP Sc . Here, the effectiveness of ovine rPrP mutants at codon 136 and peptides derived from this region were assessed for their ability to inhibit PrP Sc replication, using protein misfolding cyclic amplification (PMCA). Based on a rPrP VRQ (rVRQ) genotype background (positions 136, 154 and 171) and mutations at position 136, the most effective inhibitors were V136R, V136K and V136P mutants, with IC50 values of 2–11 nM; activities up to 57 times more potent than rVRQ. rRRQ was also shown to inhibit a range of ruminant prion amplification reactions including with distinct prion strain seeds and substrate PRNP genotypes. The rRRQ was also shown to effectively protect Rov9 cells from scrapie infection when applied at 250 nM. The study demonstrates for the first time that the rPrP sequence can be mutated at sites known to be involved in prion disease susceptibility, to produce inhibitors with improved efficacy.
2022-04-13 | Serpin Signatures in Prion and Alzheimer’s Diseases
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.
2021-12-10 | Upregulation of brain hepcidin in prion diseases.
Accumulation of redox-active iron in human sporadic Creutzfeldt-Jakob disease (sCJD) brain tissue and scrapie-infected mouse brains has been demonstrated previously. Here, we explored whether upregulation of local hepcidin secreted within the brain is the underlying cause of iron accumulation and associated toxicity. Using scrapie-infected mouse brains, we demonstrate transcriptional upregulation of hepcidin relative to controls. As a result, ferroportin (Fpn), the downstream effector of hepcidin and the only known iron export protein was downregulated, and ferritin, an iron storage protein was upregulated, suggesting increased intracellular iron. A similar transcriptional and translational upregulation of hepcidin, and decreased expression of Fpn and an increase in ferritin expression was observed in sCJD brain tissue. Further evaluation in human neuroblastoma cells (M17) exposed to synthetic mini-hepcidin showed downregulation of Fpn, upregulation of ferritin, and an increase in reactive oxygen species (ROS), resulting in cytotoxicity in a dose-dependent manner. Similar effects were noted in primary neurons isolated from mouse brain. As in M17 cells, primary neurons accumulated ferritin and ROS, and showed toxicity at five times lower concentration of mini-hepcidin. These observations suggest that upregulation of brain hepcidin plays a significant role in iron accumulation and associated neurotoxicity in human and animal prion disorders.
small molecules
2026-08-10 | Formic acid treatment drastically reduces sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease infectivity in histological samples as tested in a high-sensitivity mouse bioassay.
Formic acid treatment is widely used in diagnostic neuropathology to reduce the infectivity of prion-containing tissues; however, quantitative in vivo evidence supporting its effectiveness under routine laboratory conditions remains limited. Here, we assessed the impact of formalin fixation and formic acid treatment on the infectivity of type 1 sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD) prions using highly sensitive transgenic mouse models overexpressing human-PrP M129 (Hu-Tg340) or bovine PrP (Bo-Tg110). Brain tissues were processed under conditions closely resembling standard histopathological workflows and tested as untreated, formalin-fixed or formalin-plus-formic-acid-treated inocula. Untreated samples produced short incubation times and full attack rates, whereas formalin fixation caused only a modest prolongation of incubation times. In contrast, formic acid treatment markedly extended incubation times and reduced attack rates for sCJD. Based on incubation-time interpolation, the estimated infectivity reductions were on the order of 4.4 log₁₀ for vCJD and 5 log₁₀ for sCJD. These estimates indicate a major reduction in infectious titre under the conditions tested, although residual infectivity was still detected. The findings support formic acid treatment as an important risk-reduction step in routine neuropathology workflows for the two prion strains examined.
2026-04-07 | Ferroptosis-related mechanisms in prion diseases provide insights into neurodegeneration and reveal therapeutic implications.
Prion diseases are a group of fatal neurodegenerative disorders caused by misfolded proteins. Understanding the regulatory networks of ferroptosis in prion diseases could unveil new diagnostic and therapeutic strategies. To explore this, we systematically evaluated ferroptosis-associated alterations across human sporadic Creutzfeldt-Jakob disease (sCJD) brain samples, the ME7-infected mouse model, and in vitro using PrP106-126-treated SH-SY5Y cells. In sCJD patients, we observed a significant decrease in GPX4 expression, accompanied by elevated lipid peroxidation, as confirmed by malondialdehyde assays. Furthermore, in vitro experiments using PrP106-126-treated cells confirmed that ferroptosis-related mechanisms actively contribute to cell death, characterized by elevated lipid peroxidation, reactive oxygen species, and increased intracellular Fe2+ levels, as well as diminished glutathione activity. Critically, pharmacological inhibition with ferrostatin-1 effectively mitigated this neurotoxicity, consistent with a ferroptosis-related mechanism. To validate these findings in vivo, we demonstrated that ME7-infected mice exhibited significantly lower levels of GPX4 and SLC7A11, which correlated with increased 4-hydroxynonenal and neuronal damage. Finally, bioinformatic analysis of the GSE124571 dataset identified a distinct transcriptomic signature of 130 differentially expressed ferroptosis-related genes in sCJD patients. These results collectively suggest that ferroptosis-associated alterations are involved in prion-associated neurodegeneration, offering valuable pathophysiological insights into disease progression.
2026-01-01 | PRION BIOLOGY AND CREUTZFELDT–JAKOB DISEASE: FROM MISFOLDED PROTEINS TO CLINICAL IMPLICATIONS
Creutzfeldt–Jakob disease (CJD) is a rare, fatal, and rapidly progressive neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies, characterized by the accumulation of misfolded prion proteins (PrP^Sc) in the central nervous system. The pathogenesis involves conformational conversion of the normal cellular prion protein (PrP^C) into its pathogenic isoform, initiating a cascade of neurotoxicity, neuronal loss, and spongiform changes. CJD manifests in sporadic, genetic, and acquired forms, with clinical features including rapidly progressive dementia, myoclonus, visual disturbances, and cerebellar ataxia. Advances in diagnostic modalities—such as real-time quaking-induced conversion (RT-QuIC), magnetic resonance imaging (MRI) signal changes, and cerebrospinal fluid biomarkers—have improved early detection, yet definitive diagnosis remains postmortem through neuropathological examination. Despite intensive research, no curative therapy exists; management remains supportive, underscoring the urgency for therapeutic breakthroughs. Recent studies have explored anti-prion compounds, immunotherapeutic approaches, and gene-targeting strategies, showing promise in preclinical models. This review synthesizes current knowledge on prion biology, molecular mechanisms of disease, diagnostic advancements, and emerging therapeutic strategies, with the aim of bridging the gap between bench research and clinical application. Understanding the intricate relationship between prion protein misfolding and neurodegeneration may pave the way for targeted interventions in CJD and related prion diseases.
2025-12-08 | Oligosaccharyltransferase (OST) complex inhibition effectively treats rodent and human prions
ABSTRACT Prion diseases are invariably fatal neurodegenerative diseases that occur when the prion protein misfolds into a pathogenic form. There are currently no clinical treatments or cures for prion disease. Current challenges in the development of prion therapeutics include prion strain specificity, which can cause the emergence of drug-resistant prions, and lack of efficacy in treating human prions despite promising results in rodent models. Here we identify a novel therapeutic target for prion disease: the oligosaccharyltransferase (OST) complex. The OST complex is responsible for transferring the mature glycan to the acceptor polypeptide during Nglycosylation. We found that inhibiting OST effectively treats rodent prions in various dividing and non-dividing cell types. Importantly, we also demonstrate efficacy in treating human sCJD prions in non-dividing cerebral organoids. Inhibition of OST results in a 50% reduction in cell surface expression of the prion protein, PrP C . In addition, lysates of cells treated with the OST inhibitor NGI-1 were unable to amplify PrP Sc seeds in Protein Misfolding Cyclic Amplification (PMCA) reactions. In summary, our results identify OST as a novel therapeutic target that regulates both the abundance of cell surface PrP C as well as its ability to convert into multiple strains of PrP Sc , including human prions, in various in vitro systems. Author Summary Prion diseases, such as Creutzfeldt–Jakob disease, are fatal brain disorders caused when a normal protein (PrP C ) misfolds into a harmful form that spreads through the brain. There are no effective treatments, and drug development has been hampered by “strain” differences in prions that can lead to resistance and by therapies that work in rodents but not in humans. This study identifies a new treatment target: the oligosaccharyltransferase (OST) complex, a cellular machine that adds sugar groups to proteins. Blocking OST with a small molecule (NGI1) limited prion growth in multiple types of rodent cells, including non-dividing cells, and— critically—also worked against human sporadic CJD prions in laboratory-grown human brain organoids. OST inhibition cut the amount of normal prion protein on cell surfaces in half, reducing the raw material available to convert into the disease-causing form. In addition, extracts from NGI-1–treated cells could no longer drive prion formation in a sensitive lab amplification test. These results suggest that targeting OST may offer a new strategy that works across different prion strains, including human ones.
2025-09-22 | Initial Manic Presentation in Creutzfeldt-Jakob Disease: A Case Report.
BACKGROUND Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative condition caused by misfolded prion proteins. It most commonly presents with rapidly progressive dementia and neurological deterioration. While psychiatric symptoms are not unusual in the early stages of CJD, it is very uncommon for the disease to begin with manic features as the primary presentation. CASE REPORT We describe the case of a 65-year-old woman who initially developed symptoms consistent with mania. These included an elevated mood, emotional instability, and insomnia. Over time, her clinical condition worsened, and she began to experience hallucinations, along with a noticeable motor decline. Due to the atypical nature of her initial symptoms, she was first treated for viral encephalitis, which contributed to a delay in establishing the correct diagnosis. Subsequent investigations played a key role in clarifying the underlying pathology. Brain magnetic resonance imaging (MRI) revealed characteristic findings of CJD, including cortical ribboning and changes in the basal ganglia. Electroencephalography (EEG) showed periodic sharp-wave complexes, further supporting the diagnosis. Cerebrospinal fluid analysis tested positive for prion protein using real-time quaking-induced conversion (RT-QuIC), confirming a final diagnosis of sporadic CJD (sCJD). CONCLUSIONS Although rare, mania can be an early sign of CJD. This case illustrates the diagnostic challenges that arise when psychiatric symptoms dominate the initial clinical picture. It emphasizes the importance of maintaining a broad differential diagnosis when evaluating new-onset psychiatric symptoms in older adults, especially when these symptoms are accompanied by a rapid decline in cognition or motor function. Early consideration of CJD in such scenarios may help expedite diagnosis, avoid unnecessary treatments, and provide clarity for patients and families facing a progressive and life-limiting illness.
antibodies
2026-06-30 | A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt-Jakob disease prions.
Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.
2025-07-04 | Review of Creutzfeldt-Jakob Disease: Biology, Development, and Current Research
Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disorder caused by prions-abnormally folded proteins.Unlike typical infectious agents, prions lack genetic material and are exceptionally resistant to sterilization.CJD manifests through progressive neurological and psychological symptoms, ultimately resulting in death.It can develop sporadically, genetically, iatrogenically, or through contaminated food.Although no cure currently exists, recent research has shown promising results, including the recent human trial of the monoclonal antibody PRN100.This paper provides an overview of prion biology, the development of CJD, and recent therapeutic research.
2024-04-23 | Interactions between Cytokines and the Pathogenesis of Prion Diseases: Insights and Implications
Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt-Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood-brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions.
2022-05-06 | Endogenous retroviruses promote prion-like spreading of proteopathic seeds
Abstract Endogenous retroviruses, remnants of viral germline infections, make up a substantial proportion of the mammalian genome. While usually epigenetically silenced, retroelements can become upregulated in neurodegenerative diseases associated with protein aggregation, such as amyotrophic lateral sclerosis and tauopathies. Here we demonstrate that spontaneous upregulation of endogenous retrovirus gene expression drastically affects the dissemination of protein aggregates between murine cells in culture. Viral glycoprotein Env mediates membrane association between donor and recipient cells and promotes the intercellular transfer of protein aggregates packaged into extracellular vesicles. Proteopathic seed spreading can be inhibited by neutralizing antibodies targeting Env as well as drugs inhibiting viral protein processing. Importantly, we show that also overexpression of a human endogenous retrovirus Env elevates intercellular spreading of pathological Tau. Our data highlight the potential influence of endogenous retroviral proteins on protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.
2022-04-25 | Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme.
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. 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. 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). 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. The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.
other
2026-03-09 | Prion Diseases as Attractor Medicine: Conformational False Attractors, Cross-Species Resistance, and Drug Target Derivation from the Identity Axis Framework
This paper extends the Identity Axis Framework (R = A/H) — previously applied to cancer, neurodegeneration, and psychiatric disease — to prion diseases, establishing a new table class: the protein conformational false attractor (Class 2 / Level 4). We derive why prion diseases are geometrically distinct from all other entries in the Attractor Medicine table: the unit of identity failure is not a cell but a single protein molecule, and the false attractor (PrPSc, beta-sheet conformation) is thermodynamically self-maintaining without an enzymatic Hub. The R_PRION coordinate (energy barrier to false conformation / PrPSc templating efficiency) is introduced and validated against the cross-species resistance data: dogs (D163), rabbits (S174), horses (S167), and the Fore people of Papua New Guinea (G127V, Mead et al., NEJM 2015). The Fore G127V evolution — complete prion resistance from a single amino acid change in four generations — is identified as the clearest documented case of natural selection raising R_PRION by reinforcing the Identity Anchor of a protein. The standard Tier 2 Hub inhibitor drug logic fails for prion disease (the Hub is not a separate enzyme but the misfolded conformation itself), and the correct drug logic is derived to be substrate removal (ION717 PRNP-ASO, Phase 1/2, 2024) combined with conformation stabilisation (anle138b). A Tier 3 intervention — base editing G127V in PRNP — is derived as a permanent synthetic equivalent of the Fore evolution. The document introduces the four-level taxonomy of identity failure (gene regulatory, circuit connectivity, temporal/phase, protein conformational), unifies the Level 4 drug platform across all propagating protein diseases (prion, Alzheimer's tau, Parkinson's alpha-syn, Huntington's mHTT, ALS TDP-43), and derives the coupling between lifespan extension and sporadic CJD risk as a direct implication of the anti-aging framework. Nine claims are verified against published evidence; three novel predictions are locked with this timestamp.
2025-11-26 | A dividing cell model for stable propagation and curing of bona fide human sporadic Creutzfeldt-Jakob Disease prions
Abstract Prions are assemblies of misfolded proteins that cause transmissible, progressive neurodegenerative disease in humans and other mammals. Human prion diseases have particular public health and biological significance, both due to their transmissibility between hosts, and the mechanisms they share with many other neurodegenerative conditions. However, their study has been considerably impeded by the absence of a cell-based system capable of reproducibly propagating and quantifying bona fide human prion infectivity, which has been a goal for several decades. Here, we describe the first robust, cell-based assay of human prion infectivity in dividing cells. We found that CAD5 cells expressing human prion protein instead of the endogenous mouse prion protein, replicate human prion infectivity from brain samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD) expressing valine at codon 129 of the prion protein gene. Moreover, these cells quantify human prion infectivity with similar sensitivity to the current gold standard animal bioassay, at a fraction of the cost and time, maintain persistent infection that can be cured with an anti-prion treatment, and can be adapted for therapeutic screening. This novel system permits direct cell-based quantification and investigation of human prion infectivity for the first time.
2025-04-30 | Prion Disease in Animals and Humans: Exploring, Pathogenesis, Transmission
Prion diseases are fatal neurodegenerative disorders affecting both humans and animals, caused by misfolded prion proteins that induce the conversion of normal cellular prion protein into pathogenic forms. This misfolded protein resist degradation, accumulates in the brain, and induces neuronal death, leading to rapid cognitive and motor decline. This project aims to investigate the mechanisms of pathogenesis, transmission pathways, and early detection methods for these transmissible spongiform encephalopathy (TSEs). Stanley Prusiner’s team advanced this “protein-only hypothesis “, coining the term prion (1982) as a nucleic acid –resistant proteinaceous particle by 1985. A total of 27,872 cases of prion disease (PrD) and 24,623 cases of Creutzfeldt-Jakob disease (sCJD) have been reported across 34 countries with accessible annual data. Prion disease, including Creutzfeldt-Jakob disease (CJD), fatal insomnia and Kuru, can occur sporadically, be inherited, or result from exposure to infected material. Although rare, these disease are invariably fatal, with no current cure available. Recent advancement in diagnostic methods, such as Real-Time Quaking-Induces conversion (RT-QuIC) and Magnetic Resonance Imaging (MRI), offers hope for earlier diagnosis. Emerging treatment approaches, including antisense oligonucleotides (ASOs) and tetracyclic compound’s, provide optimism for possible therapies. By synthesizing current knowledge and identifying gaps in research, this project seeks to contribute to a deeper understanding of prion diseases and inform future diagnostic and therapeutic developments.
2024-06-08 | CLINICALLY PROBABLE SPORADIC CREUTZFELDT JAKOB DISEASE (CJD)
Creutzfeldt-Jakob Disease (CJD) stands at the forefront of neurodegenerative disorders, characterized by rapid progression and devastating neurological deterioration. This review encapsulates the current understanding of CJD, encompassing its epidemiology, etiology, pathogenesis, clinical manifestations, and diagnostic modalities. While classified into sporadic, familial, iatrogenic, and variant forms, sporadic CJD remains the most prevalent, with a complex interplay of genetic, environmental, and stochastic factors contributing to its onset. The misfolding of cellular prion proteins (PrPC) into pathological conformers (PrPSc) serves as a hallmark event, instigating a cascade of neurotoxic processes, including protein aggregation, synaptic dysfunction, and neuronal death. Clinically, CJD manifests with a triad of progressive dementia, myoclonus, and characteristic electroencephalographic findings, presenting diagnostic challenges due to its heterogeneous symptomatology and overlap with other neurodegenerative conditions. However, advancements in biomarker identification, neuroimaging techniques, and cerebrospinal fluid analyses hold promise for enhancing early detection and differential diagnosis. Despite extensive research, therapeutic interventions for CJD remain limited, primarily focusing on symptomatic management and palliative care. Nevertheless, emerging strategies targeting prion propagation, immunotherapy, and gene editing offer potential avenues for disease modification and treatment. The profound impact of CJD on affected individuals, families, and healthcare systems underscores the imperative for continued research efforts aimed at unraveling its intricate pathophysiology and developing effective interventions to alleviate its burden.
2024-01-08 | Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.
vaccines
2023-02-11 | Vaccines for prion diseases: a realistic goal?
Abstract Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrP C ) into the pathological PrP Sc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrP C and PrP Sc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrP C -directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.
2014-09-30 | Prospects for safe and effective vaccines against prion diseases
Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrPSc) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt–Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.
2013-10-20 | Evidence for Prion-Like Mechanisms in Several Neurodegenerative Diseases: Potential Implications for Immunotherapy
Transmissible spongiform encephalopathies (TSEs) are fatal, untreatable neurodegenerative diseases. While the impact of TSEs on human health is relatively minor, these diseases are having a major influence on how we view, and potentially treat, other more common neurodegenerative disorders. Until recently, TSEs encapsulated a distinct category of neurodegenerative disorder, exclusive in their defining characteristic of infectivity. It now appears that similar mechanisms of self-propagation may underlie other proteinopathies such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. This link is of scientific interest and potential therapeutic importance as this route of self-propagation offers conceptual support and guidance for vaccine development efforts. Specifically, the existence of a pathological, self-promoting isoform offers a rational vaccine target. Here, we review the evidence of prion-like mechanisms within a number of common neurodegenerative disorders and speculate on potential implications and opportunities for vaccine development.
2012-03-01 | Could immunomodulation be used to prevent prion diseases?
All prion diseases are currently without effective treatment and are universally fatal. The underlying pathogenesis of prion diseases (prionoses) is related to an autocatalytic conformational conversion of PrPC (C for cellular) to a pathological and infectious conformer known as PrPSc (Sc for scrapie) or PrPRes (Res for proteinase K resistant). The past experience with variant Creutzfeldt–Jakob disease, which originated from bovine spongiform encephalopathy, as well as the ongoing epidemic of chronic wasting disease has highlighted the necessity for effective prophylactic and/or therapeutic approaches. Human prionoses are most commonly sporadic, and hence therapy is primarily directed to stop progression; however, in animals the majority of prionoses are infectious and, as a result, the emphasis is on prevention of transmission. These infectious prionoses are most commonly acquired via the alimentary tract as a major portal of infectious agent entry, making mucosal immunization a potentially attractive method to produce a local immune response that can partially or completely prevent prion entry across the gut barrier, while at the same time producing a modulated systemic immunity that is unlikely to be associated with toxicity. A critical factor in any immunomodulatory methodology that targets a self-antigen is the need to delicately balance an effective humoral immune response with potential autoimmune inflammatory toxicity. The ongoing epidemic of chronic wasting disease affecting the USA and Korea, with the potential to spread to human populations, highlights the need for such immunomodulatory approaches.
2010-11-24 | Immunomodulation for prion and prion-related diseases
Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformational change of a normal self protein called cellular prion protein to a pathological and infectious conformer known as scrapie prion protein (PrPSc). Currently, all prion diseases lack effective treatment and are universally fatal. Past experiences with bovine spongiform encephalopathy and variant Creutzfeldt–Jakob disease mainly in Europe, as well as the current epidemic of chronic wasting disease in North America, have highlighted the need to develop prophylactic and/or therapeutic approaches. In Alzheimer’s disease that, like prion disease, is a conformational neurodegenerative disorder, both passive and active immunization has been shown to be highly effective in model animals at preventing disease and cognitive deficits, with emerging data from human trials suggesting that this approach is able to reduce amyloid-related pathology. However, any immunomodulatory approach aimed at a self-antigen has to finely balance an effective humoral immune response with potential autoimmune toxicity. The prion diseases most commonly acquired by infection typically have the alimentary tract as a portal of infectious agent entry. This makes mucosal immunization a potentially attractive method to produce a local immune response that partially or completely prevents prion entry across the gut barrier, while at the same time producing modulated systemic immunity that is unlikely to be associated with toxicity. Our results using an attenuated Salmonella vaccine strain expressing the prion protein showed that mucosal vaccination can protect against prion infection from a peripheral source, suggesting the feasibility of this approach. It is also possible to develop active and/or passive immunomodulatory approaches that more specifically target PrPSc or target the shared pathological conformer found in numerous conformational disorders. Such approaches could have a significant impact on many of the common age-associated dementias.
proteins
2025-04-30 | Abnormal Expression of Proteolytic Stress-Related Proteins and Protective Effect of Fibrinolytic Enzymes in Prion Diseases.
Prion diseases are fatal, irreversible, and infectious neurodegenerative diseases caused by proteinase K-resistant prion protein (PrPSc). Against PrPSc, several endogenous proteases involved in cellular degradation mechanisms can be activated to remove PrPSc. However, since PrPSc shows proteinase K resistance, we presumed that undegradable PrPSc induces positive feedback on the overactivation of the cellular degradation mechanisms and is correlated with proteolytic stress and exacerbation of the progression of prion diseases. We investigated the expression pattern of proteolytic stress-related proteins in the brains of ME7 scrapie-infected mice at 7 months postinfection and sporadic Creutzfeldt-Jakob disease (CJD) patients using western blotting and immunohistochemistry (IHC). In addition, we analyzed the 3D structure and binding complexes of prion protein (PrP) with nattokinase and lumbrokinase using in silico programs, including SWISS-MODEL and HawkDock. To fundamentally reduce proteolytic stress by the degradation of PrPSc, we performed an in vitro evaluation of the PrPSc degradation abilities of fibrinolytic enzymes, including nattokinase and lumbrokinase. Furthermore, we assessed the protective effects of nattokinase and lumbrokinase in ME7 scrapie-infected mice. We observed an abnormal accumulation of proteolytic stress-related proteins, including CD10, cathepsin B, cathepsin D, and matrix metalloproteinase 9 (MMP9), in the brains of ME7 scrapie-infected mice and sporadic CJD patients. In addition, we identified that nattokinase and lumbrokinase can stably bind to PrP. Furthermore, we identified significant in vitro degradation of PrPSc derived from ME7 scrapie-infected mice and sporadic CJD patients by nattokinase and lumbrokinase. Last, we found in vivo protective effects of nattokinase and lumbrokinase against prion disease in ME7 scrapie-infected mice. To the best of our knowledge, this is the first report on the identification of proteolytic stress-related novel potential biomarkers and the therapeutic potential of nattokinase and lumbrokinase for prion diseases.
2023-08-01 | Different tau fibril types reduce prion level in chronically and de novo infected cells
Neurodegenerative diseases are often characterized by the codeposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An example is represented by prion diseases, where the classical deposition of the aberrant conformational isoform of the prion protein (PrPSc) can be associated with tau insoluble species, which are usually involved in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion diseases is still a matter of debate. Recently, the cellular form of the prion protein, PrPC, has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau, and α-synuclein has been reported, and it has been linked to several neurotoxic behaviors exerted by these proteins. We have previously shown that the treatment of chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels. In this work, we further explored this mechanism by using another tau construct that includes the sequence that forms the core of Alzheimer's disease tau filaments in vivo to obtain a distinct fibril type. Despite a difference of six amino acids, these two constructs form fibrils characterized by distinct biochemical and biological features. However, their effects on PrPSc reduction were comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the pathological conversion event. Our results suggest PrPC as receptor for different types of tau fibrils and point out a role of tau amyloid fibrils in preventing the pathological PrPC to PrPSc conformational change.
2022-07-25 | Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation
Abstract Prion diseases are progressive neurodegenerative disorders with no effective therapeutics. A central event leading to the pathology in the diseases is the conversion of PrP C into PrP Sc and its accumulation in the central nervous system. Previous studies demonstrated that PrP C , recombinant PrP (rPrP) and PrP peptides can inhibit the formation of PrP Sc . Here, the effectiveness of ovine rPrP mutants at codon 136 and peptides derived from this region were assessed for their ability to inhibit PrP Sc replication, using protein misfolding cyclic amplification (PMCA). Based on a rPrP VRQ (rVRQ) genotype background (positions 136, 154 and 171) and mutations at position 136, the most effective inhibitors were V136R, V136K and V136P mutants, with IC50 values of 2–11 nM; activities up to 57 times more potent than rVRQ. rRRQ was also shown to inhibit a range of ruminant prion amplification reactions including with distinct prion strain seeds and substrate PRNP genotypes. The rRRQ was also shown to effectively protect Rov9 cells from scrapie infection when applied at 250 nM. The study demonstrates for the first time that the rPrP sequence can be mutated at sites known to be involved in prion disease susceptibility, to produce inhibitors with improved efficacy.
2022-04-13 | Serpin Signatures in Prion and Alzheimer’s Diseases
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.
2021-12-10 | Upregulation of brain hepcidin in prion diseases.
Accumulation of redox-active iron in human sporadic Creutzfeldt-Jakob disease (sCJD) brain tissue and scrapie-infected mouse brains has been demonstrated previously. Here, we explored whether upregulation of local hepcidin secreted within the brain is the underlying cause of iron accumulation and associated toxicity. Using scrapie-infected mouse brains, we demonstrate transcriptional upregulation of hepcidin relative to controls. As a result, ferroportin (Fpn), the downstream effector of hepcidin and the only known iron export protein was downregulated, and ferritin, an iron storage protein was upregulated, suggesting increased intracellular iron. A similar transcriptional and translational upregulation of hepcidin, and decreased expression of Fpn and an increase in ferritin expression was observed in sCJD brain tissue. Further evaluation in human neuroblastoma cells (M17) exposed to synthetic mini-hepcidin showed downregulation of Fpn, upregulation of ferritin, and an increase in reactive oxygen species (ROS), resulting in cytotoxicity in a dose-dependent manner. Similar effects were noted in primary neurons isolated from mouse brain. As in M17 cells, primary neurons accumulated ferritin and ROS, and showed toxicity at five times lower concentration of mini-hepcidin. These observations suggest that upregulation of brain hepcidin plays a significant role in iron accumulation and associated neurotoxicity in human and animal prion disorders.
small molecules
2026-08-10 | Formic acid treatment drastically reduces sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease infectivity in histological samples as tested in a high-sensitivity mouse bioassay.
Formic acid treatment is widely used in diagnostic neuropathology to reduce the infectivity of prion-containing tissues; however, quantitative in vivo evidence supporting its effectiveness under routine laboratory conditions remains limited. Here, we assessed the impact of formalin fixation and formic acid treatment on the infectivity of type 1 sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD) prions using highly sensitive transgenic mouse models overexpressing human-PrP M129 (Hu-Tg340) or bovine PrP (Bo-Tg110). Brain tissues were processed under conditions closely resembling standard histopathological workflows and tested as untreated, formalin-fixed or formalin-plus-formic-acid-treated inocula. Untreated samples produced short incubation times and full attack rates, whereas formalin fixation caused only a modest prolongation of incubation times. In contrast, formic acid treatment markedly extended incubation times and reduced attack rates for sCJD. Based on incubation-time interpolation, the estimated infectivity reductions were on the order of 4.4 log₁₀ for vCJD and 5 log₁₀ for sCJD. These estimates indicate a major reduction in infectious titre under the conditions tested, although residual infectivity was still detected. The findings support formic acid treatment as an important risk-reduction step in routine neuropathology workflows for the two prion strains examined.
2026-04-07 | Ferroptosis-related mechanisms in prion diseases provide insights into neurodegeneration and reveal therapeutic implications.
Prion diseases are a group of fatal neurodegenerative disorders caused by misfolded proteins. Understanding the regulatory networks of ferroptosis in prion diseases could unveil new diagnostic and therapeutic strategies. To explore this, we systematically evaluated ferroptosis-associated alterations across human sporadic Creutzfeldt-Jakob disease (sCJD) brain samples, the ME7-infected mouse model, and in vitro using PrP106-126-treated SH-SY5Y cells. In sCJD patients, we observed a significant decrease in GPX4 expression, accompanied by elevated lipid peroxidation, as confirmed by malondialdehyde assays. Furthermore, in vitro experiments using PrP106-126-treated cells confirmed that ferroptosis-related mechanisms actively contribute to cell death, characterized by elevated lipid peroxidation, reactive oxygen species, and increased intracellular Fe2+ levels, as well as diminished glutathione activity. Critically, pharmacological inhibition with ferrostatin-1 effectively mitigated this neurotoxicity, consistent with a ferroptosis-related mechanism. To validate these findings in vivo, we demonstrated that ME7-infected mice exhibited significantly lower levels of GPX4 and SLC7A11, which correlated with increased 4-hydroxynonenal and neuronal damage. Finally, bioinformatic analysis of the GSE124571 dataset identified a distinct transcriptomic signature of 130 differentially expressed ferroptosis-related genes in sCJD patients. These results collectively suggest that ferroptosis-associated alterations are involved in prion-associated neurodegeneration, offering valuable pathophysiological insights into disease progression.
2026-01-01 | PRION BIOLOGY AND CREUTZFELDT–JAKOB DISEASE: FROM MISFOLDED PROTEINS TO CLINICAL IMPLICATIONS
Creutzfeldt–Jakob disease (CJD) is a rare, fatal, and rapidly progressive neurodegenerative disorder belonging to the group of transmissible spongiform encephalopathies, characterized by the accumulation of misfolded prion proteins (PrP^Sc) in the central nervous system. The pathogenesis involves conformational conversion of the normal cellular prion protein (PrP^C) into its pathogenic isoform, initiating a cascade of neurotoxicity, neuronal loss, and spongiform changes. CJD manifests in sporadic, genetic, and acquired forms, with clinical features including rapidly progressive dementia, myoclonus, visual disturbances, and cerebellar ataxia. Advances in diagnostic modalities—such as real-time quaking-induced conversion (RT-QuIC), magnetic resonance imaging (MRI) signal changes, and cerebrospinal fluid biomarkers—have improved early detection, yet definitive diagnosis remains postmortem through neuropathological examination. Despite intensive research, no curative therapy exists; management remains supportive, underscoring the urgency for therapeutic breakthroughs. Recent studies have explored anti-prion compounds, immunotherapeutic approaches, and gene-targeting strategies, showing promise in preclinical models. This review synthesizes current knowledge on prion biology, molecular mechanisms of disease, diagnostic advancements, and emerging therapeutic strategies, with the aim of bridging the gap between bench research and clinical application. Understanding the intricate relationship between prion protein misfolding and neurodegeneration may pave the way for targeted interventions in CJD and related prion diseases.
2025-12-08 | Oligosaccharyltransferase (OST) complex inhibition effectively treats rodent and human prions
ABSTRACT Prion diseases are invariably fatal neurodegenerative diseases that occur when the prion protein misfolds into a pathogenic form. There are currently no clinical treatments or cures for prion disease. Current challenges in the development of prion therapeutics include prion strain specificity, which can cause the emergence of drug-resistant prions, and lack of efficacy in treating human prions despite promising results in rodent models. Here we identify a novel therapeutic target for prion disease: the oligosaccharyltransferase (OST) complex. The OST complex is responsible for transferring the mature glycan to the acceptor polypeptide during Nglycosylation. We found that inhibiting OST effectively treats rodent prions in various dividing and non-dividing cell types. Importantly, we also demonstrate efficacy in treating human sCJD prions in non-dividing cerebral organoids. Inhibition of OST results in a 50% reduction in cell surface expression of the prion protein, PrP C . In addition, lysates of cells treated with the OST inhibitor NGI-1 were unable to amplify PrP Sc seeds in Protein Misfolding Cyclic Amplification (PMCA) reactions. In summary, our results identify OST as a novel therapeutic target that regulates both the abundance of cell surface PrP C as well as its ability to convert into multiple strains of PrP Sc , including human prions, in various in vitro systems. Author Summary Prion diseases, such as Creutzfeldt–Jakob disease, are fatal brain disorders caused when a normal protein (PrP C ) misfolds into a harmful form that spreads through the brain. There are no effective treatments, and drug development has been hampered by “strain” differences in prions that can lead to resistance and by therapies that work in rodents but not in humans. This study identifies a new treatment target: the oligosaccharyltransferase (OST) complex, a cellular machine that adds sugar groups to proteins. Blocking OST with a small molecule (NGI1) limited prion growth in multiple types of rodent cells, including non-dividing cells, and— critically—also worked against human sporadic CJD prions in laboratory-grown human brain organoids. OST inhibition cut the amount of normal prion protein on cell surfaces in half, reducing the raw material available to convert into the disease-causing form. In addition, extracts from NGI-1–treated cells could no longer drive prion formation in a sensitive lab amplification test. These results suggest that targeting OST may offer a new strategy that works across different prion strains, including human ones.
2025-09-22 | Initial Manic Presentation in Creutzfeldt-Jakob Disease: A Case Report.
BACKGROUND Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative condition caused by misfolded prion proteins. It most commonly presents with rapidly progressive dementia and neurological deterioration. While psychiatric symptoms are not unusual in the early stages of CJD, it is very uncommon for the disease to begin with manic features as the primary presentation. CASE REPORT We describe the case of a 65-year-old woman who initially developed symptoms consistent with mania. These included an elevated mood, emotional instability, and insomnia. Over time, her clinical condition worsened, and she began to experience hallucinations, along with a noticeable motor decline. Due to the atypical nature of her initial symptoms, she was first treated for viral encephalitis, which contributed to a delay in establishing the correct diagnosis. Subsequent investigations played a key role in clarifying the underlying pathology. Brain magnetic resonance imaging (MRI) revealed characteristic findings of CJD, including cortical ribboning and changes in the basal ganglia. Electroencephalography (EEG) showed periodic sharp-wave complexes, further supporting the diagnosis. Cerebrospinal fluid analysis tested positive for prion protein using real-time quaking-induced conversion (RT-QuIC), confirming a final diagnosis of sporadic CJD (sCJD). CONCLUSIONS Although rare, mania can be an early sign of CJD. This case illustrates the diagnostic challenges that arise when psychiatric symptoms dominate the initial clinical picture. It emphasizes the importance of maintaining a broad differential diagnosis when evaluating new-onset psychiatric symptoms in older adults, especially when these symptoms are accompanied by a rapid decline in cognition or motor function. Early consideration of CJD in such scenarios may help expedite diagnosis, avoid unnecessary treatments, and provide clarity for patients and families facing a progressive and life-limiting illness.
antibodies
2026-06-30 | A scalable, dividing cell model for the robust propagation and quantification of human sporadic Creutzfeldt-Jakob disease prions.
Prion diseases represent a unique biological paradigm with mechanistic parallels to other neurodegenerative conditions like Alzheimer's and Parkinson's diseases. However, the study of human prion pathobiology and the development of effective therapeutics has been severely constrained by the inability to propagate human prions in dividing cells-forcing reliance on costly and slow animal bioassays. Here, we report the generation of EKV cells-a humanized cell model which supports the robust, indefinite propagation of sporadic Creutzfeldt-Jakob disease (sCJD) prions. We demonstrate that these cells replicate bona fide human prion infectivity in culture-cell lysates induce lethal neurodegeneration in humanized mice that is clinically and neuropathologically indistinguishable from inoculation with sCJD-infected brain tissue. We use EKV cells to develop the Human Prion Assay (HPA), which quantifies sCJD infectivity with sensitivity comparable to gold-standard mouse bioassay, while reducing the experimental timeline from years to weeks. Furthermore, we demonstrate that established sCJD infection can be cured by an anti-prion protein antibody, validating the system as a high-throughput platform for drug discovery. This model bridges a critical translational gap, offering a renewable alternative to animal bioassays, a paradigm to dissect the biology of human sCJD prion disease and screen for therapeutic agents.
2025-07-04 | Review of Creutzfeldt-Jakob Disease: Biology, Development, and Current Research
Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disorder caused by prions-abnormally folded proteins.Unlike typical infectious agents, prions lack genetic material and are exceptionally resistant to sterilization.CJD manifests through progressive neurological and psychological symptoms, ultimately resulting in death.It can develop sporadically, genetically, iatrogenically, or through contaminated food.Although no cure currently exists, recent research has shown promising results, including the recent human trial of the monoclonal antibody PRN100.This paper provides an overview of prion biology, the development of CJD, and recent therapeutic research.
2024-04-23 | Interactions between Cytokines and the Pathogenesis of Prion Diseases: Insights and Implications
Transmissible Spongiform Encephalopathies (TSEs), including prion diseases such as Bovine Spongiform Encephalopathy (Mad Cow Disease) and variant Creutzfeldt-Jakob Disease, pose unique challenges to the scientific and medical communities due to their infectious nature, neurodegenerative effects, and the absence of a cure. Central to the progression of TSEs is the conversion of the normal cellular prion protein (PrPC) into its infectious scrapie form (PrPSc), leading to neurodegeneration through a complex interplay involving the immune system. This review elucidates the current understanding of the immune response in prion diseases, emphasizing the dual role of the immune system in both propagating and mitigating the disease through mechanisms such as glial activation, cytokine release, and blood-brain barrier dynamics. We highlight the differential cytokine profiles associated with various prion strains and stages of disease, pointing towards the potential for cytokines as biomarkers and therapeutic targets. Immunomodulatory strategies are discussed as promising avenues for mitigating neuroinflammation and delaying disease progression. This comprehensive examination of the immune response in TSEs not only advances our understanding of these enigmatic diseases but also sheds light on broader neuroinflammatory processes, offering hope for future therapeutic interventions.
2022-05-06 | Endogenous retroviruses promote prion-like spreading of proteopathic seeds
Abstract Endogenous retroviruses, remnants of viral germline infections, make up a substantial proportion of the mammalian genome. While usually epigenetically silenced, retroelements can become upregulated in neurodegenerative diseases associated with protein aggregation, such as amyotrophic lateral sclerosis and tauopathies. Here we demonstrate that spontaneous upregulation of endogenous retrovirus gene expression drastically affects the dissemination of protein aggregates between murine cells in culture. Viral glycoprotein Env mediates membrane association between donor and recipient cells and promotes the intercellular transfer of protein aggregates packaged into extracellular vesicles. Proteopathic seed spreading can be inhibited by neutralizing antibodies targeting Env as well as drugs inhibiting viral protein processing. Importantly, we show that also overexpression of a human endogenous retrovirus Env elevates intercellular spreading of pathological Tau. Our data highlight the potential influence of endogenous retroviral proteins on protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.
2022-04-25 | Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme.
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. 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. 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). 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. 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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2026-03-09 | Prion Diseases as Attractor Medicine: Conformational False Attractors, Cross-Species Resistance, and Drug Target Derivation from the Identity Axis Framework
This paper extends the Identity Axis Framework (R = A/H) — previously applied to cancer, neurodegeneration, and psychiatric disease — to prion diseases, establishing a new table class: the protein conformational false attractor (Class 2 / Level 4). We derive why prion diseases are geometrically distinct from all other entries in the Attractor Medicine table: the unit of identity failure is not a cell but a single protein molecule, and the false attractor (PrPSc, beta-sheet conformation) is thermodynamically self-maintaining without an enzymatic Hub. The R_PRION coordinate (energy barrier to false conformation / PrPSc templating efficiency) is introduced and validated against the cross-species resistance data: dogs (D163), rabbits (S174), horses (S167), and the Fore people of Papua New Guinea (G127V, Mead et al., NEJM 2015). The Fore G127V evolution — complete prion resistance from a single amino acid change in four generations — is identified as the clearest documented case of natural selection raising R_PRION by reinforcing the Identity Anchor of a protein. The standard Tier 2 Hub inhibitor drug logic fails for prion disease (the Hub is not a separate enzyme but the misfolded conformation itself), and the correct drug logic is derived to be substrate removal (ION717 PRNP-ASO, Phase 1/2, 2024) combined with conformation stabilisation (anle138b). A Tier 3 intervention — base editing G127V in PRNP — is derived as a permanent synthetic equivalent of the Fore evolution. The document introduces the four-level taxonomy of identity failure (gene regulatory, circuit connectivity, temporal/phase, protein conformational), unifies the Level 4 drug platform across all propagating protein diseases (prion, Alzheimer's tau, Parkinson's alpha-syn, Huntington's mHTT, ALS TDP-43), and derives the coupling between lifespan extension and sporadic CJD risk as a direct implication of the anti-aging framework. Nine claims are verified against published evidence; three novel predictions are locked with this timestamp.
2025-11-26 | A dividing cell model for stable propagation and curing of bona fide human sporadic Creutzfeldt-Jakob Disease prions
Abstract Prions are assemblies of misfolded proteins that cause transmissible, progressive neurodegenerative disease in humans and other mammals. Human prion diseases have particular public health and biological significance, both due to their transmissibility between hosts, and the mechanisms they share with many other neurodegenerative conditions. However, their study has been considerably impeded by the absence of a cell-based system capable of reproducibly propagating and quantifying bona fide human prion infectivity, which has been a goal for several decades. Here, we describe the first robust, cell-based assay of human prion infectivity in dividing cells. We found that CAD5 cells expressing human prion protein instead of the endogenous mouse prion protein, replicate human prion infectivity from brain samples of patients with sporadic Creutzfeldt-Jakob disease (sCJD) expressing valine at codon 129 of the prion protein gene. Moreover, these cells quantify human prion infectivity with similar sensitivity to the current gold standard animal bioassay, at a fraction of the cost and time, maintain persistent infection that can be cured with an anti-prion treatment, and can be adapted for therapeutic screening. This novel system permits direct cell-based quantification and investigation of human prion infectivity for the first time.
2025-04-30 | Prion Disease in Animals and Humans: Exploring, Pathogenesis, Transmission
Prion diseases are fatal neurodegenerative disorders affecting both humans and animals, caused by misfolded prion proteins that induce the conversion of normal cellular prion protein into pathogenic forms. This misfolded protein resist degradation, accumulates in the brain, and induces neuronal death, leading to rapid cognitive and motor decline. This project aims to investigate the mechanisms of pathogenesis, transmission pathways, and early detection methods for these transmissible spongiform encephalopathy (TSEs). Stanley Prusiner’s team advanced this “protein-only hypothesis “, coining the term prion (1982) as a nucleic acid –resistant proteinaceous particle by 1985. A total of 27,872 cases of prion disease (PrD) and 24,623 cases of Creutzfeldt-Jakob disease (sCJD) have been reported across 34 countries with accessible annual data. Prion disease, including Creutzfeldt-Jakob disease (CJD), fatal insomnia and Kuru, can occur sporadically, be inherited, or result from exposure to infected material. Although rare, these disease are invariably fatal, with no current cure available. Recent advancement in diagnostic methods, such as Real-Time Quaking-Induces conversion (RT-QuIC) and Magnetic Resonance Imaging (MRI), offers hope for earlier diagnosis. Emerging treatment approaches, including antisense oligonucleotides (ASOs) and tetracyclic compound’s, provide optimism for possible therapies. By synthesizing current knowledge and identifying gaps in research, this project seeks to contribute to a deeper understanding of prion diseases and inform future diagnostic and therapeutic developments.
2024-06-08 | CLINICALLY PROBABLE SPORADIC CREUTZFELDT JAKOB DISEASE (CJD)
Creutzfeldt-Jakob Disease (CJD) stands at the forefront of neurodegenerative disorders, characterized by rapid progression and devastating neurological deterioration. This review encapsulates the current understanding of CJD, encompassing its epidemiology, etiology, pathogenesis, clinical manifestations, and diagnostic modalities. While classified into sporadic, familial, iatrogenic, and variant forms, sporadic CJD remains the most prevalent, with a complex interplay of genetic, environmental, and stochastic factors contributing to its onset. The misfolding of cellular prion proteins (PrPC) into pathological conformers (PrPSc) serves as a hallmark event, instigating a cascade of neurotoxic processes, including protein aggregation, synaptic dysfunction, and neuronal death. Clinically, CJD manifests with a triad of progressive dementia, myoclonus, and characteristic electroencephalographic findings, presenting diagnostic challenges due to its heterogeneous symptomatology and overlap with other neurodegenerative conditions. However, advancements in biomarker identification, neuroimaging techniques, and cerebrospinal fluid analyses hold promise for enhancing early detection and differential diagnosis. Despite extensive research, therapeutic interventions for CJD remain limited, primarily focusing on symptomatic management and palliative care. Nevertheless, emerging strategies targeting prion propagation, immunotherapy, and gene editing offer potential avenues for disease modification and treatment. The profound impact of CJD on affected individuals, families, and healthcare systems underscores the imperative for continued research efforts aimed at unraveling its intricate pathophysiology and developing effective interventions to alleviate its burden.
2024-01-08 | Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6-/- and Stx6+/- mice differed by 12 days relative to wildtype. Similarly, in Stx6-/- mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6-/- animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6-/- mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.
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Drug Discovery Landscape
2 orphan drug designations for Sporadic Creutzfeldt-Jakob disease.
2 orphan drug designations for Sporadic Creutzfeldt-Jakob disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
N,N'-([Cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinyl]acetamide) | small molecules | EMA | 2024-07-25 | — | RegSmart Life Science AB |
Pentamer formyl thiophene acetic acid | small molecules | EMA | 2017-06-20 | — | NeuroScios GmbH |
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