RARE DISEASE
Fatal familial insomnia
Fatal familial insomnia
Fatal familial insomnia
Drug discovery
0
drugs
With orphan designations
Overview
Fatal Familial Insomnia (FFI) is a rare, autosomal dominant prion disease caused by a PRNP gene mutation (D178N with methionine at codon 129). It presents with progressive intractable insomnia, autonomic hyperactivity (tachycardia, hypertension, hyperhidrosis), and rapid neuropsychiatric decline, including ataxia, hallucinations, and dementia. Diagnosis relies on genetic testing, polysomnography (showing disrupted sleep architecture), and thalamic hypometabolism on PET imaging. No disease-modifying therapies exist; management is palliative, focusing on symptom relief. Prognosis is invariably fatal, with median survival of 7–36 months [1][2][6][10].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
80 drug discovery papers about Fatal familial insomnia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
80 drug discovery papers about Fatal familial insomnia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-02-02 | Dreams as Sheaf Probes: The Transmission Gear Between Cache Identity and Context Identity
Four published instruments describe identity and consciousness at different temporal resolu- tions: the First-in Cache Identity (FCI) formalizes the self as a rolling buffer with anti-aliasing and monotone fictionalization at the micro-scale (seconds to minutes); the Sheaf-of-Contexts Identity (SCI) formalizes the self as a global section glued from context-local sections with ˇ Cech obstruction at the macro-scale (months to lifetime); the Individuals as Invariants frame- work provides the phenomenal field Φ and the CHIA composite-head architecture; and the Sleep-as-GLUE monograph (Monograph 98) establishes sleep as the canonical GLUE step in the Intercalation Lemma applied to the consciousness mezzanine. What has been missing is the transmission gear: the explicit mechanism that moves data from the FCI cache (RAM) to the SCI sheaf (map). We prove that sleep is that compiler. The wake–sleep cycle implements a discrete deployment schedule in which waking generates FCI local sections (the diffs) and sleep runs the GLUE operation that integrates them into the SCI global section (the merge). Dreams are the thermodynamic exhaust of this compilation—not hallucinations, not messages, but the visible residue of sheaf-compatibility audits conducted at blur β <β⋆ with guards deliberately relaxed. Dream content is Murphy-scheduled: it targets high-Ob/Lc overlaps where the identity sheaf is weakest. Dream phenomenology—vividness without epistemic worth, confidence without fidelity, discontinuity without detection—follows from FCI’s monotone fictionalization theorem operating at extreme parameters during the GLUE phase. We derive falsifiable predictions for dream content bias, vividness–blur coupling, post-learning replay specificity, and pathological modes (night terrors as cohomological write failures, insomnia as residual catastrophe, fatal familial insomnia as mezzanine evaporation, lucid dreaming as partial guard restoration). The synthesis completes the three-scale invariant theory of identity: FCI at the micro-scale, sleep at the meso-scale, SCI at the macro-scale, unified by the Intercalation Lemma and metered by the Murphy horiz
2025-05-14 | Doxycycline: An essential tool for Alzheimer's disease.
The identification of active interventions in neurodegenerative disorders is a major challenge in neurology; the use of repurposed drugs may represent a valuable strategy. Tetracyclines, a second generation of antibiotic molecules, offer various potential applications. Following an anecdotal observation of the potential anti-amyloidogenic activity of iododoxorubicin, the search for chemical analogs with a better safety profile led to tetracyclines. Their heterocyclic structures with a planar conformation interfere with b-sheet amyloid formation. Thus, doxycycline, a derivative with favorable blood-brain barrier penetration, emerged as a strong candidate to combat peripheral and central amyloidosis. In particular, we tested the anti-prion activity of doxycycline in vitro and in vivo experiments, confirming its capacity to disrupt or inhibit the formation of prion protein aggregates associated with pathological events. Treatment with doxycycline in human subjects with prion - related encephalopathies yielded contradictory results, suggesting that a preventive approach is a more favorable condition to verify efficacy; a clinical trial involving subjects at genetic risk of developing fatal familial insomnia, exposed to doxycycline for ten years, is currently ongoing. The anti-amyloidogenic capacity of doxycycline, combined with its safety profile in long-term treatment, has suggested its use in peripheral amyloidosis, which was tested with positive results. A specific interaction with β-amyloid or α-synuclein oligomers, as well as tau aggregation has also been demonstrated. More recently, the action of doxycycline has been extended to its anti-inflammatory and antioxidant capacities. In particular, the anti-inflammatory activity of doxycycline may explain the drug 's efficacy in numerous experimental models where protein misfolding has been associated with neuroinflammation, including Huntington's and Parkinson' s diseases. Thus, the pleiotropic action of doxycycline appears to be an interesting tool for addressing progressive neuronal dysfunction in multifactorial neurodegenerative diseases. The application of precision medicine principles to doxycycline treatment represents the best strategy to determine its efficacy. These aspects are illustrated here concerning another pleiotropic tetracycline, minocycline.
2024-06-03 | Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds
PrP Sc , a misfolded, aggregation-prone isoform of the cellular prion protein (PrP C ), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrP Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrP C is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrP C and discuss our recent identification of Zn(II)-BnPyP, a PrP C -targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrP C may lead toward the development of a new class of dual mechanism anti-prion compounds.
2024-04-01 | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease
Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrP Sc propagation in vitro . None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrP Sc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.
2024-02-28 | Sleepless in Captivity: Insomnia Kills the Von Economo Neurons
Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. The role of dysfunctional mitochondria in psychopathology is well-established, however, the association of these organelles with sleep physiology is novel. Indeed, reducing neuronal oxidative stress by importing mitochondria from astrocytes, may be the purpose of human slumber. This model may explain mitochondrial dysfunction during anesthesia as well as in the rare genetic disease, fatal familial insomnia. In this narrative review, we focus on the salience network of the brain, a common denominator for insomnia, neuropsychiatric and neurodegenerative disorders. We also discuss mitochondria-protecting strategies, including membrane lipid replacement, natural and synthetic phenazine and phenothiazine derivatives.
oligonucleotides
2026-02-12 | Modern view on prion diseases of the nervous system
Prion diseases (PDs) are rare neurodegenerative disorders caused by abnormal forms of the PrP protein, which can induce conformational changes in normal proteins and lead to progressive degeneration of nerve tissue. These diseases are characterized by a long incubation period and high mortality. The importance of studying PDs stems from the need to develop diagnostic and preventive methods, as well as the search for eff ective therapeutic agents. The article presents information on the mechanisms of damage to the nervous system, on the key forms of PDs (Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker syndrome, fatal familial insomnia, and others), presents modern diagnostic methods with an indication of their sensitivity and specifi city, and also considers promising areas of therapy (antisense oligonucleotides, antibodies, aggregation inhibitors, activation of autophagy, gene therapy).
2001-12-01 | DNA Converts Cellular Prion Protein into the β-Sheet Conformation and Inhibits Prion Peptide Aggregation
The main hypothesis for prion diseases proposes that the cellular protein (PrP(C)) can be altered into a misfolded, beta-sheet-rich isoform (PrP(Sc)), which in most cases undergoes aggregation. In an organism infected with PrP(Sc), PrP(C) is converted into the beta-sheet form, generating more PrP(Sc). We find that sequence-specific DNA binding to recombinant murine prion protein (mPrP-(23-231)) converts it from an alpha-helical conformation (cellular isoform) into a soluble, beta-sheet isoform similar to that found in the fibrillar state. The recombinant murine prion protein and prion domains bind with high affinity to DNA sequences. Several double-stranded DNA sequences in molar excess above 2:1 (pH 4.0) or 0.5:1 (pH 5.0) completely inhibit aggregation of prion peptides, as measured by light scattering, fluorescence, and circular dichroism spectroscopy. However, at a high concentration, fibers (or peptide aggregates) can rescue the peptide bound to the DNA, converting it to the aggregating form. Our results indicate that a macromolecular complex of prion-DNA may act as an intermediate for the formation of the growing fiber. We propose that host nucleic acid may modulate the delicate balance between the cellular and the misfolded conformations by reducing the protein mobility and by making the protein-protein interactions more likely. In our model, the infectious material would act as a seed to rescue the protein bound to nucleic acid. Accordingly, DNA would act on the one hand as a guardian of the Sc conformation, preventing its propagation, but on the other hand may catalyze Sc conversion and aggregation if a threshold level is exceeded.
1996-12-01 | Induction of antibodies against human prion proteins (PrP) by DNA-mediated immunization of mice
Prion diseases are neurodegenerative disorders, affecting humans and animals. The human diseases include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). To generate monospecific antisera against human prion proteins we have immunized mice with DNA coding for different human prion proteins. We constructed immunization vectors expressing individual genotypes of either the cellular prion gene (PRNP) or mutant forms under appropriate promoters. This approach avoids the preparation of infectious material for immunization. To circumvent immunological tolerance prion protein-deficient PrP00 mice were used for the DNA-mediated immunization. Thereby monospecific sera were raised capable of specifically precipitating in vitro synthesized human prion proteins. With prion protein-specific peptide ELISAs, we found that antibodies are predominantly directed against the octapeptide repeat region and to a lesser extent to regions comprising the signal peptide, the neurotoxic domain or the GPI anchor. In contrast, prion gene-positive (PrP+/+) BALB/c mice immunized under the same experimental conditions as the PrP00 mice did not respond with antibody formation against the human prion protein. This is the first report clearly showing that immune competent prion protein-deficient mice react with a vigorous polyclonal immune response after DNA-mediated immunization with human prion gene sequences.
antibodies
2026-01-25 | Genetic causes and modifiers of prion diseases.
Prion diseases are transmissible neurodegenerative diseases caused by misfolding of prion protein (PrP). All inherited prion diseases, including genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia, are caused by pathogenic mutations in the prion protein gene (PRNP). The mutation partly dictates age at disease onset and clinical phenotype, presumably by its effects on the misfolding of PrP, but the clinical features can be highly variable even within the same pedigree. In sporadic prion diseases, genetic factors also play pivotal roles, as polymorphisms of PrP affect susceptibility, strain specificity, and disease progression. Additionally, emerging evidence highlights genetic modifiers outside PRNP that regulate disease susceptibility, implicating protein trafficking and lipid metabolism. Because individuals at genetic risk can be identified long before symptom onset, a distinctive opportunity exists for early or even presymptomatic therapeutic intervention. The unequivocal and well understood molecular target that is PrP, together with the development of diagnostic biomarkers, could create a favourable research setting for disease-modifying treatments.
2025-07-04 | A review on current theories and potential therapies for prion diseases.
Prion diseases are neurodegenerative disorders that affect both humans and animals. They are commonly characterized by the absence of DNA and RNA and are distinguished from inherited or infectious forms. The cellular prion proteins (PrPC) misfold and accumulate into their pathogenic isoforms in these diseases. Disease conditions like Gerstmann-Straussler-Scheinker disease, Creutzfeldt-Jakob disease, and fatal familial insomnia are all related to prion proteins. The majority of the patients with prion disorders have a life expectancy of less than a year. An effective therapeutic approach for these prion diseases remains a formidable challenge. This review focuses on novel therapeutic approaches, such as antibody-based treatments that aim to stop normal proteins from changing into the harmful form of the prion protein (PrPSc). Additionally, the review discusses the potential of RNA interference, antisense oligonucleotides, anti-aggregation compounds, β-sheet breakers, and stem cell-based therapies in addressing prion diseases.
2019-02-01 | Clinical trials of prion disease therapeutics
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
2016-06-01 | Prion diseases: immunotargets and therapy
Abstract: Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP Sc in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4 + T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP Sc conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4 + cells to initiate an immune response. Adoptive transfer of CD4 + T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases. Keywords: neurodegeneration, immunization, spongiform encephalopathies, PrP C , PrP Sc , tansmissible spongiform encephalopathies Creutzfeldt-Jacob disease, dendritice cells, Alzheimer disease
2014-08-01 | Advances in the development of antibody-based immunotherapy against prion disease
Abstract: Prion disease, also known as transmissible spongiform encephalopathies, is the name given to a group of neurodegenerative disorders. Transformation of the cellular prion protein (PrP C ) into self-replicating and proteinase K-resistant PrP (PrP Sc ) in the brain is the pathological hallmark of the disease. All prion disorders have a rapidly progressive and lethal course after onset, and no effective therapy currently exists. Antibody-based immunotherapy has been extensively investigated in neurodegenerative disorders associated with protein misfolding, including prion disease. This review summarizes and outlines the developments in and limitations of active and passive immunization approaches to the prevention and treatment for prion disease. In addition, the potential of these therapeutic strategies is discussed. Keywords: transmissible spongiform encephalopathies, neurodegenerative, prion protein, proteinase K-resistant PrP
proteins
2026-01-01 | Advancing prion diagnostics: full-length human E200K RT-QuIC substrate facilitates prion detection in tear fluid and improves sensitivity in cerebrospinal fluid
Abstract The real-time quaking-induced conversion (RT-QuIC) assay has revolutionized prion disease diagnosis by detecting amyloidogenic PrP conformers in different tissue types and body fluids. Recently, we achieved a breakthrough by detecting amyloidogenic PrP conformers in tear fluid (TF), a non-invasive biofluid, warranting further evaluation. We refined our RT-QuIC protocol to assess seeding conversion efficiency using various recombinant substrates, including full-length human (FL Hu), and mutant versions linked to genetic prion diseases, such as E200K and D178N, in both CSF and TF samples. Our study included patients with sporadic and familial prion diseases. FL Hu E200K showed the highest seeding efficiency in cerebrospinal fluid (CSF), with sensitivity increasing from 78 to 93% for symptomatic Creutzfeldt–Jakob disease (CJD) and from 19 to 75% for fatal familial insomnia (FFI) compared with the hamster-sheep substrate. For tear fluid, diagnostic sensitivity was 85% for sCJD and 64% for symptomatic genetic prion diseases, the assay was also able to detect amyloidogenic PrP in 57% of the healthy mutation carriers (HMC, persons at risk without symptoms). We validated the diagnostic accuracy of the TF RT-QuIC from our previous study (cohort 1) in a second independent study. Additionally, we confirmed that TF RT-QuIC requires FL Hu E200K substrates since hamster-sheep failed in detection of seeding activity in tears. Notably, only 1 out of 184 controls without prion disease tested positive. Studies comparing different disease stages (early vs. late) showed that later stages produced a stronger signal response. Our study demonstrates that the FL Hu E200K rec PrP substrate improves RT-QuIC sensitivity in CSF diagnostics and validates the reliable detection of seeding activity in TF in two cohorts as well as in HMC.
2020-07-28 | Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion*
Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the beta-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2-H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2-H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.
other
2025-01-08 | Fatal familial insomnia: A new case description with response to thoracic sympathetic nerve thermocoagulation and stellate ganglion block.
Fatal familial insomnia (FFI) is a rare autosomal dominant neurodegenerative disorder characterized by rapidly progressive dementia, severe sleep disturbances, and autonomic dysfunction. The clinical manifestations of FFI can exhibit substantial variations, making it crucial to rule out other conditions, such as autoimmune encephalitis and Creutzfeldt-Jakob disease, during early diagnosis. In this study, we describe the case of a 58-year-old man who experienced persistent insomnia, autonomic symptoms, gait instability, and rapidly progressive dementia. Polysomnography revealed considerable alterations brain positron emission tomography/computed tomography showed no significant abnormal changes and cerebrospinal fluid analysis indicated a slight elevation in protein levels. Results of tests for autoimmune encephalitis antibodies were negative. The presence of the prion protein gene D178N mutation was confirmed through genetic testing and in conjunction with the patient's clinical manifestations, a diagnosis of FFI was established. Owing to severe autonomic neuropathy and intractable hyponatremia resulting from excessive sweating, therapeutic interventions, including thoracic sympathetic nerve thermocoagulation and stellate ganglion block, were attempted. These treatments initially led to symptomatic improvements, such as reduced sweating and amelioration of hyponatremia; however, sweating persisted, albeit to a lesser extent. Despite these interventions, the patient's condition deteriorated, leading to death 16 months after symptom onset owing to progressive agrypnia excitata, worsening dementia, and gait instability. This case underscores the current lack of effective treatments for FFI and highlights the urgent need for further research on this debilitating disorder.
small molecules
2026-02-02 | Dreams as Sheaf Probes: The Transmission Gear Between Cache Identity and Context Identity
Four published instruments describe identity and consciousness at different temporal resolu- tions: the First-in Cache Identity (FCI) formalizes the self as a rolling buffer with anti-aliasing and monotone fictionalization at the micro-scale (seconds to minutes); the Sheaf-of-Contexts Identity (SCI) formalizes the self as a global section glued from context-local sections with ˇ Cech obstruction at the macro-scale (months to lifetime); the Individuals as Invariants frame- work provides the phenomenal field Φ and the CHIA composite-head architecture; and the Sleep-as-GLUE monograph (Monograph 98) establishes sleep as the canonical GLUE step in the Intercalation Lemma applied to the consciousness mezzanine. What has been missing is the transmission gear: the explicit mechanism that moves data from the FCI cache (RAM) to the SCI sheaf (map). We prove that sleep is that compiler. The wake–sleep cycle implements a discrete deployment schedule in which waking generates FCI local sections (the diffs) and sleep runs the GLUE operation that integrates them into the SCI global section (the merge). Dreams are the thermodynamic exhaust of this compilation—not hallucinations, not messages, but the visible residue of sheaf-compatibility audits conducted at blur β <β⋆ with guards deliberately relaxed. Dream content is Murphy-scheduled: it targets high-Ob/Lc overlaps where the identity sheaf is weakest. Dream phenomenology—vividness without epistemic worth, confidence without fidelity, discontinuity without detection—follows from FCI’s monotone fictionalization theorem operating at extreme parameters during the GLUE phase. We derive falsifiable predictions for dream content bias, vividness–blur coupling, post-learning replay specificity, and pathological modes (night terrors as cohomological write failures, insomnia as residual catastrophe, fatal familial insomnia as mezzanine evaporation, lucid dreaming as partial guard restoration). The synthesis completes the three-scale invariant theory of identity: FCI at the micro-scale, sleep at the meso-scale, SCI at the macro-scale, unified by the Intercalation Lemma and metered by the Murphy horiz
2025-05-14 | Doxycycline: An essential tool for Alzheimer's disease.
The identification of active interventions in neurodegenerative disorders is a major challenge in neurology; the use of repurposed drugs may represent a valuable strategy. Tetracyclines, a second generation of antibiotic molecules, offer various potential applications. Following an anecdotal observation of the potential anti-amyloidogenic activity of iododoxorubicin, the search for chemical analogs with a better safety profile led to tetracyclines. Their heterocyclic structures with a planar conformation interfere with b-sheet amyloid formation. Thus, doxycycline, a derivative with favorable blood-brain barrier penetration, emerged as a strong candidate to combat peripheral and central amyloidosis. In particular, we tested the anti-prion activity of doxycycline in vitro and in vivo experiments, confirming its capacity to disrupt or inhibit the formation of prion protein aggregates associated with pathological events. Treatment with doxycycline in human subjects with prion - related encephalopathies yielded contradictory results, suggesting that a preventive approach is a more favorable condition to verify efficacy; a clinical trial involving subjects at genetic risk of developing fatal familial insomnia, exposed to doxycycline for ten years, is currently ongoing. The anti-amyloidogenic capacity of doxycycline, combined with its safety profile in long-term treatment, has suggested its use in peripheral amyloidosis, which was tested with positive results. A specific interaction with β-amyloid or α-synuclein oligomers, as well as tau aggregation has also been demonstrated. More recently, the action of doxycycline has been extended to its anti-inflammatory and antioxidant capacities. In particular, the anti-inflammatory activity of doxycycline may explain the drug 's efficacy in numerous experimental models where protein misfolding has been associated with neuroinflammation, including Huntington's and Parkinson' s diseases. Thus, the pleiotropic action of doxycycline appears to be an interesting tool for addressing progressive neuronal dysfunction in multifactorial neurodegenerative diseases. The application of precision medicine principles to doxycycline treatment represents the best strategy to determine its efficacy. These aspects are illustrated here concerning another pleiotropic tetracycline, minocycline.
2024-06-03 | Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds
PrP Sc , a misfolded, aggregation-prone isoform of the cellular prion protein (PrP C ), is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals. PrP Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, posing challenges for the development of effective therapies. Since PrP C is the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity, it represents an attractive therapeutic target for prion diseases. In this minireview, we briefly outline the approaches to target PrP C and discuss our recent identification of Zn(II)-BnPyP, a PrP C -targeting porphyrin with an unprecedented bimodal mechanism of action. We argue that in-depth understanding of the molecular mechanism by which Zn(II)-BnPyP targets PrP C may lead toward the development of a new class of dual mechanism anti-prion compounds.
2024-04-01 | Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease
Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrP Sc propagation in vitro . None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrP Sc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.
2024-02-28 | Sleepless in Captivity: Insomnia Kills the Von Economo Neurons
Forensic hospitals throughout the country house individuals with severe mental illness and history of criminal violations. Insomnia affects 67.4% of hospitalized patients with chronic neuropsychiatric disorders, indicating that these conditions may hijack human somnogenic pathways. Conversely, somnolence is a common adverse effect of many antipsychotic drugs, further highlighting a common etiopathogenesis. The role of dysfunctional mitochondria in psychopathology is well-established, however, the association of these organelles with sleep physiology is novel. Indeed, reducing neuronal oxidative stress by importing mitochondria from astrocytes, may be the purpose of human slumber. This model may explain mitochondrial dysfunction during anesthesia as well as in the rare genetic disease, fatal familial insomnia. In this narrative review, we focus on the salience network of the brain, a common denominator for insomnia, neuropsychiatric and neurodegenerative disorders. We also discuss mitochondria-protecting strategies, including membrane lipid replacement, natural and synthetic phenazine and phenothiazine derivatives.
oligonucleotides
2026-02-12 | Modern view on prion diseases of the nervous system
Prion diseases (PDs) are rare neurodegenerative disorders caused by abnormal forms of the PrP protein, which can induce conformational changes in normal proteins and lead to progressive degeneration of nerve tissue. These diseases are characterized by a long incubation period and high mortality. The importance of studying PDs stems from the need to develop diagnostic and preventive methods, as well as the search for eff ective therapeutic agents. The article presents information on the mechanisms of damage to the nervous system, on the key forms of PDs (Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker syndrome, fatal familial insomnia, and others), presents modern diagnostic methods with an indication of their sensitivity and specifi city, and also considers promising areas of therapy (antisense oligonucleotides, antibodies, aggregation inhibitors, activation of autophagy, gene therapy).
2001-12-01 | DNA Converts Cellular Prion Protein into the β-Sheet Conformation and Inhibits Prion Peptide Aggregation
The main hypothesis for prion diseases proposes that the cellular protein (PrP(C)) can be altered into a misfolded, beta-sheet-rich isoform (PrP(Sc)), which in most cases undergoes aggregation. In an organism infected with PrP(Sc), PrP(C) is converted into the beta-sheet form, generating more PrP(Sc). We find that sequence-specific DNA binding to recombinant murine prion protein (mPrP-(23-231)) converts it from an alpha-helical conformation (cellular isoform) into a soluble, beta-sheet isoform similar to that found in the fibrillar state. The recombinant murine prion protein and prion domains bind with high affinity to DNA sequences. Several double-stranded DNA sequences in molar excess above 2:1 (pH 4.0) or 0.5:1 (pH 5.0) completely inhibit aggregation of prion peptides, as measured by light scattering, fluorescence, and circular dichroism spectroscopy. However, at a high concentration, fibers (or peptide aggregates) can rescue the peptide bound to the DNA, converting it to the aggregating form. Our results indicate that a macromolecular complex of prion-DNA may act as an intermediate for the formation of the growing fiber. We propose that host nucleic acid may modulate the delicate balance between the cellular and the misfolded conformations by reducing the protein mobility and by making the protein-protein interactions more likely. In our model, the infectious material would act as a seed to rescue the protein bound to nucleic acid. Accordingly, DNA would act on the one hand as a guardian of the Sc conformation, preventing its propagation, but on the other hand may catalyze Sc conversion and aggregation if a threshold level is exceeded.
1996-12-01 | Induction of antibodies against human prion proteins (PrP) by DNA-mediated immunization of mice
Prion diseases are neurodegenerative disorders, affecting humans and animals. The human diseases include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). To generate monospecific antisera against human prion proteins we have immunized mice with DNA coding for different human prion proteins. We constructed immunization vectors expressing individual genotypes of either the cellular prion gene (PRNP) or mutant forms under appropriate promoters. This approach avoids the preparation of infectious material for immunization. To circumvent immunological tolerance prion protein-deficient PrP00 mice were used for the DNA-mediated immunization. Thereby monospecific sera were raised capable of specifically precipitating in vitro synthesized human prion proteins. With prion protein-specific peptide ELISAs, we found that antibodies are predominantly directed against the octapeptide repeat region and to a lesser extent to regions comprising the signal peptide, the neurotoxic domain or the GPI anchor. In contrast, prion gene-positive (PrP+/+) BALB/c mice immunized under the same experimental conditions as the PrP00 mice did not respond with antibody formation against the human prion protein. This is the first report clearly showing that immune competent prion protein-deficient mice react with a vigorous polyclonal immune response after DNA-mediated immunization with human prion gene sequences.
antibodies
2026-01-25 | Genetic causes and modifiers of prion diseases.
Prion diseases are transmissible neurodegenerative diseases caused by misfolding of prion protein (PrP). All inherited prion diseases, including genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia, are caused by pathogenic mutations in the prion protein gene (PRNP). The mutation partly dictates age at disease onset and clinical phenotype, presumably by its effects on the misfolding of PrP, but the clinical features can be highly variable even within the same pedigree. In sporadic prion diseases, genetic factors also play pivotal roles, as polymorphisms of PrP affect susceptibility, strain specificity, and disease progression. Additionally, emerging evidence highlights genetic modifiers outside PRNP that regulate disease susceptibility, implicating protein trafficking and lipid metabolism. Because individuals at genetic risk can be identified long before symptom onset, a distinctive opportunity exists for early or even presymptomatic therapeutic intervention. The unequivocal and well understood molecular target that is PrP, together with the development of diagnostic biomarkers, could create a favourable research setting for disease-modifying treatments.
2025-07-04 | A review on current theories and potential therapies for prion diseases.
Prion diseases are neurodegenerative disorders that affect both humans and animals. They are commonly characterized by the absence of DNA and RNA and are distinguished from inherited or infectious forms. The cellular prion proteins (PrPC) misfold and accumulate into their pathogenic isoforms in these diseases. Disease conditions like Gerstmann-Straussler-Scheinker disease, Creutzfeldt-Jakob disease, and fatal familial insomnia are all related to prion proteins. The majority of the patients with prion disorders have a life expectancy of less than a year. An effective therapeutic approach for these prion diseases remains a formidable challenge. This review focuses on novel therapeutic approaches, such as antibody-based treatments that aim to stop normal proteins from changing into the harmful form of the prion protein (PrPSc). Additionally, the review discusses the potential of RNA interference, antisense oligonucleotides, anti-aggregation compounds, β-sheet breakers, and stem cell-based therapies in addressing prion diseases.
2019-02-01 | Clinical trials of prion disease therapeutics
Prion-related encephalopathies or transmissible spongiform encephalopathies (TSEs) are a group of rare progressive neurodegenerative disorders that are invariably fatal with often only six months elapsing from diagnosis to patient death. This makes the development of effective therapeutic strategies challenging. Nonetheless, compounds have been identified in animal models of TSE that prolong survival and, in some instances, eradicate the disease. These have been tested in the clinic, although with modest or negative outcomes. While little progress has been made over the last decade, new findings that include the ability to identify prion aggregates at low levels in biological fluids and cells may lead to the development of early-stage biomarkers for TSE. An increased focus on immunotherapeutic approaches to TSE may result in the development of novel preventive approaches for TSE.
2016-06-01 | Prion diseases: immunotargets and therapy
Abstract: Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt–Jakob disease, variant Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP Sc in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4 + T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP Sc conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4 + cells to initiate an immune response. Adoptive transfer of CD4 + T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases. Keywords: neurodegeneration, immunization, spongiform encephalopathies, PrP C , PrP Sc , tansmissible spongiform encephalopathies Creutzfeldt-Jacob disease, dendritice cells, Alzheimer disease
2014-08-01 | Advances in the development of antibody-based immunotherapy against prion disease
Abstract: Prion disease, also known as transmissible spongiform encephalopathies, is the name given to a group of neurodegenerative disorders. Transformation of the cellular prion protein (PrP C ) into self-replicating and proteinase K-resistant PrP (PrP Sc ) in the brain is the pathological hallmark of the disease. All prion disorders have a rapidly progressive and lethal course after onset, and no effective therapy currently exists. Antibody-based immunotherapy has been extensively investigated in neurodegenerative disorders associated with protein misfolding, including prion disease. This review summarizes and outlines the developments in and limitations of active and passive immunization approaches to the prevention and treatment for prion disease. In addition, the potential of these therapeutic strategies is discussed. Keywords: transmissible spongiform encephalopathies, neurodegenerative, prion protein, proteinase K-resistant PrP
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2026-01-01 | Advancing prion diagnostics: full-length human E200K RT-QuIC substrate facilitates prion detection in tear fluid and improves sensitivity in cerebrospinal fluid
Abstract The real-time quaking-induced conversion (RT-QuIC) assay has revolutionized prion disease diagnosis by detecting amyloidogenic PrP conformers in different tissue types and body fluids. Recently, we achieved a breakthrough by detecting amyloidogenic PrP conformers in tear fluid (TF), a non-invasive biofluid, warranting further evaluation. We refined our RT-QuIC protocol to assess seeding conversion efficiency using various recombinant substrates, including full-length human (FL Hu), and mutant versions linked to genetic prion diseases, such as E200K and D178N, in both CSF and TF samples. Our study included patients with sporadic and familial prion diseases. FL Hu E200K showed the highest seeding efficiency in cerebrospinal fluid (CSF), with sensitivity increasing from 78 to 93% for symptomatic Creutzfeldt–Jakob disease (CJD) and from 19 to 75% for fatal familial insomnia (FFI) compared with the hamster-sheep substrate. For tear fluid, diagnostic sensitivity was 85% for sCJD and 64% for symptomatic genetic prion diseases, the assay was also able to detect amyloidogenic PrP in 57% of the healthy mutation carriers (HMC, persons at risk without symptoms). We validated the diagnostic accuracy of the TF RT-QuIC from our previous study (cohort 1) in a second independent study. Additionally, we confirmed that TF RT-QuIC requires FL Hu E200K substrates since hamster-sheep failed in detection of seeding activity in tears. Notably, only 1 out of 184 controls without prion disease tested positive. Studies comparing different disease stages (early vs. late) showed that later stages produced a stronger signal response. Our study demonstrates that the FL Hu E200K rec PrP substrate improves RT-QuIC sensitivity in CSF diagnostics and validates the reliable detection of seeding activity in TF in two cohorts as well as in HMC.
2020-07-28 | Structural and dynamical mechanisms of a naturally occurring variant of the human prion protein in preventing prion conversion*
Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the beta-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2-H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2-H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.
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2025-01-08 | Fatal familial insomnia: A new case description with response to thoracic sympathetic nerve thermocoagulation and stellate ganglion block.
Fatal familial insomnia (FFI) is a rare autosomal dominant neurodegenerative disorder characterized by rapidly progressive dementia, severe sleep disturbances, and autonomic dysfunction. The clinical manifestations of FFI can exhibit substantial variations, making it crucial to rule out other conditions, such as autoimmune encephalitis and Creutzfeldt-Jakob disease, during early diagnosis. In this study, we describe the case of a 58-year-old man who experienced persistent insomnia, autonomic symptoms, gait instability, and rapidly progressive dementia. Polysomnography revealed considerable alterations brain positron emission tomography/computed tomography showed no significant abnormal changes and cerebrospinal fluid analysis indicated a slight elevation in protein levels. Results of tests for autoimmune encephalitis antibodies were negative. The presence of the prion protein gene D178N mutation was confirmed through genetic testing and in conjunction with the patient's clinical manifestations, a diagnosis of FFI was established. Owing to severe autonomic neuropathy and intractable hyponatremia resulting from excessive sweating, therapeutic interventions, including thoracic sympathetic nerve thermocoagulation and stellate ganglion block, were attempted. These treatments initially led to symptomatic improvements, such as reduced sweating and amelioration of hyponatremia; however, sweating persisted, albeit to a lesser extent. Despite these interventions, the patient's condition deteriorated, leading to death 16 months after symptom onset owing to progressive agrypnia excitata, worsening dementia, and gait instability. This case underscores the current lack of effective treatments for FFI and highlights the urgent need for further research on this debilitating disorder.
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