40 results about "Supranuclear palsy" patented technology

The invention discloses a biomarker for auxiliary diagnosis of progressive suprakaryotic paralysis and application thereof, and relates to the technical field of biomedicine. The biomarker is a neuron-derived extracellular vesicle carrying a Tau deformable protein; the Tau deformation protein is 4R Tau or pTau181, and the Tau deformation protein is a protein with the molecular weight of 4R The invention develops a biomarker capable of assisting in diagnosing progressive suprakaryotic paralysis, and the biomarker can be used for effectively identifying a progressive suprakaryotic paralysis (PSP) patient, a Parkinson's disease (PD) patient and a healthy person (HC). Meanwhile, a progressive supranuclear paralysis diagnosis model is also constructed, the sensitivity of the multivariable logistic regression model for distinguishing PSP and HC is 95.7%, the specificity is 90.0%, and the AUC is 0.974; the sensitivity of the multivariable logistic regression model for distinguishing PSP and PD is 96.3%, the specificity is 90.0%, and the AUC is 0.968.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a microtubule associated protein tau (MAPT) gene. The MAPT RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a MAPT gene. The MAPT RNAi agents are conjugated to an antigen binding protein that may enable subcutaneous delivery of the RNAi agents by facilitating crossing of the blood brain barrier (BBB). Pharmaceutical compositions that include one or more MAPT RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MAPT RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of MAPT gene expression and a reduction in MAPT activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including Alzheimer's disease, Frontotemporal lobar degeneration dementia (FTLD), Progressive supranuclear palsy, and other tauopathies.

The invention discloses application of astrocyte-derived extracellular vesicles carrying Tau in auxiliary diagnosis of progressive suprakaryotic paralysis, and belongs to the technical field of biomedicine. The specific Tau protein antibody and the anti-glutamic acid transporter 1 antibody are labeled by fluorescence, astrocyte-derived extracellular vesicles carrying Tau in the plasma are accurately detected, PSP patients, PD patients and healthy people can be accurately distinguished by analyzing the concentration of astrocyte-derived EVs carrying Tau in the plasma, and the kit has the advantages of high sensitivity, high sensitivity, high sensitivity and the like. An efficient PSP diagnosis biomarker and a diagnosis model are provided, and a new experience method and technical support are provided for PSP diagnosis and identification.

To provide stabilization of a retromer for treating Alzheimer disease and other neurodegenerative disorders.SOLUTION: Provided is a method and a composition for increasing and stabilizing a retromer in order to treat and / or prevent Alzheimer disease and other neurodegenerative disorders. Furthermore, provided is treatment of an adenovirus base for treating Alzheimer disease (AD), and other neurodegenerative states, which are Parkinson disease (PD), neuronal ceroid lipofuscinosis (NCL), and transmissible spongiform encephalopathy (TSE or prion disease), multiple system atrophy (MSA), Down syndrome, and hereditary spastic paraplegia for example, and which are progressive supranuclear palsy (PSP), frontotemporal dementia linked to chromosomes 17q21 to 22 and subtype (FTLD-17 / FTLD-Tau) thereof, Lewy body disease (LBD), amyotrophic lateral sclerosis (AES), frontotemporal degeneration (FTD), ALS-FTD and chronic traumatic encephalopathy (CTE) for example.SELECTED DRAWING: None

The invention provides a compound of formula (I): or a pharmaceutically acceptable salt, ester, amide or carbamate thereof, or a salt of such an ester, amide or carbamate. The invention further provides uses of the compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy.

Disclosed are compounds of formula (I) wherein G1 is as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4) for use in the treatment of e.g. a neurodegenerative disorder, a movement disorder, or a brain disorder, such as e.g. Parkinson's disease, drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia, cognitive deficits associated with schizophrenia, excessive daytime sleepiness, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy, and progressive supranuclear palsy. An exemplary compound is e.g. (2,5-difluoro-4-(6-(((3aR,5s,6aS)-2-((tetrahydro-2H-pyran-4-yl)methyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyridazin-3-yl)phenyl)(imino)(methyl)-λ6-sulfanone (e.g. example 12; compound no. 7) Pharmacological data on the activity of the compounds in an mAChR M4 cell-based assay are provided (e.g. table 2).TABLE 2Human M4Cpd. No.IC50 (nM)Emin (%)*113.44239.62318.5345846575.4361883746.0385607918.43101.821186.231243.42138.63*% ACh maximum at 30 μM.

The invention relates to generation, optimization and characterisation of VHH targeted against Tau MTBD (microtubule-binding domain) with high affinity, obtained by screening from a naïve synthetic library. The inventors optimized version of a lead VHH which is able to inhibit Tau aggregation in vitro and in HEK 293 aggregation-reporting cellular model, providing a new tool in Tau immunotherapies. Accordingly the invention relates to new VHH antibody that specifically binds with high affinity Tau species, especially the epitope region involved in Tau aggregation. Moreover, the inventors found that immunization with the optimized version of this lead VHH prevented the formation of neurofibrillary tangles induced by injection of extracellular h-AD in mouse model. Thus, these specific antibodies can be used for the therapy of tauopathy disorders such as Progressive supranuclear palsy (PSP).

A compound specifically binding to an α-synuclein aggregate, and a preparation method therefor and the use thereof. Specifically, the compound binding to the α-synuclein aggregate comprises compounds as shown in formula A or sub-general formulas thereof, or stereoisomers, pharmaceutically acceptable salts, solvates or stable isotope variants thereof. The compound is a small molecule tracer, which can specifically recognize the α-synuclein aggregate, and can be used for the preparation of a drug for the treatment or diagnosis of neurodegenerative diseases (such as Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy and progressive muscular atrophy) related to the α-synuclein aggregate and other misfolded proteins.

The present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate, wherein R 1 is OH and R 2 is H or R 1 is H and R 2 is OH. The present invention further provides uses of compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits and the use of such compounds and compositions as diagnostic agents in diagnosing or monitoring the progression of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration. [Formula 1] JPEG2025540931000057.jpg34152

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or carbamate thereof, or a salt of such an ester or carbamate wherein: R1 is OH and R2 is H; or R1 is H, and R2 is OH. The invention also provides uses of compounds of formula (I) and compositions comprising compounds of formula (I), including uses of such compounds for detecting tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of diseases or disorders such as Alzheimer's disease, progressive suprakaryotic paralysis and corticobasal node degeneration, or for the prevention or treatment of diseases or disorders such as Alzheimer's disease, progressive suprakaryotic paralysis and corticobasal node degeneration. # imgabs0 #

To identify a causative gene for progressive supranuclear palsy to create effective therapeutic methods and therapeutic agents, and to provide useful means for developing the therapeutic methods and therapeutic agents.SOLUTION: In order to solve this problem, a therapeutic agent for progressive supranuclear palsy is provided, which contains a compound that inhibits expression of a filamin A gene. In addition, an evaluation system or the like using cells expressing filamin A is provided, which can be used to search and the like for the therapeutic agents or candidate agents for progressive supranuclear palsy.SELECTED DRAWING: None

Multispecific binding molecules having a first binding domain targeting a blood brain barrier target and a second binding domain targeting a neuron target, astrocyte target and / or glial cell target, and uses thereof in aiding the treatment of central nervous system diseases including neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's diseases, Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS), Frontal Temporal Dementia (FTD), autism, catalepsy, encephalitis, migraine, and Tourette's.

Disclosed are agents that include a) a binding and / or disaggregating moiety that adheres to a target polypeptide in its amyloid fibril form, and proceed to inhibit the target protein and / or disaggregate the fibril form, and b) a nanomass moiety that promotes transfer of the agent to a site of the target polypeptide. The disclosed agents can be used in methods for destabilizing a tau amyloid fibril, and for treating a tauopathy (e.g., Alzheimer's disease, progressive supranuclear palsy) in a subject.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a microtubule associated protein tau (MAPT) gene. The MAPT RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a MAPT gene. The MAPT RNAi agents are conjugated to an antigen binding protein that may enable subcutaneous delivery of the RNAi agents by facilitating crossing of the blood brain barrier (BBB). Pharmaceutical compositions that include one or more MAPT RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MAPT RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of MAPT gene expression and a reduction in MAPT activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including Alzheimer's disease, Frontotemporal lobar degeneration dementia (FTLD), Progressive supranuclear palsy, and other tauopathies.

Provided are crystalline forms of 3-(5-(4-((3,3-dimethyl-4-((1-(6-(5-(1- methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)piperazin-1- yl)methyl)piperidin-1-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidine-2, 6-dione, pharmaceutical compositions comprising the crystalline form, and their use in treating conditions associated with LRRK2, such as Parkinson's disease, dementia, Progressive Supranuclear Palsy, Huntington's disease, or neuroinflammation.

To provide compounds for effective treatment of diseases and disorders related to LRRK2, which are idiopathic PD, LRRK2 mutation associated PD (e.g., PD associated with one or more LRRK2 activated mutations), primary tauopathy (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, Hansen's disease (e.g., Hansen's disease associated with type 1 inflammatory reactions), and / or neuroinflammation, for example.SOLUTION: Provided are bifunctional compounds useful as modulators of leucine-rich repeat kinase 2 (LRRK2). Particularly, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.SELECTED DRAWING: None

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a microtubule associated protein tau (MAPT) gene. The MAPT RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of a MAPT gene. The MAPT RNAi agents are conjugated to an antigen binding protein that may enable subcutaneous delivery of the RNAi agents by facilitating crossing of the blood brain barrier (BBB). Pharmaceutical compositions that include one or more MAPT RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described MAPT RNAi agents to central nervous system (CNS) tissue, in vivo, provides for inhibition of MAPT gene expression and a reduction in MAPT activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including Alzheimer's disease, Frontotemporal lobar degeneration dementia (FTLD), Progressive supranuclear palsy, and other tauopathies.

The invention discloses the in vitro use of a non-LTR RTE biomarker, such as LINE-1, to diagnose neurodegenerative diseases, particularly tauopathies. The diagnosis is based on identifying an increase in the number of LINE-1 copies in the biological fluids of an individual, and the difference in the number of copies of a non-LTR RTE, LINE-1, per ng of DNA in a biological sample, preferably a buffy coat, between healthy subjects (Control) and ill patients. The tauopathies are: Alzheimer's Disease (EA), Mild Cognitive Impairment (DCL), Progressive Supranuclear Palsy (PSP) / Corticobasal Syndrome (SCB) and Frontotemporal Dementia (DFT). The invention also relates to a kit comprising means for detecting the biomarker in a biological sample obtained from the individual and means for comparing the levels of the biomarker of interest in the sample with a control reference obtained from healthy individuals, and relates to an in vitro method for detecting a non-LTR RTE, such as LINE-1, in a biological sample.

The invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or carbamate thereof, or a salt of such an ester or carbamate,wherein either:R1 is OH, and R2 is H; orR1 is H, and R2 is OH.The invention further provides uses of the compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration.

The invention relates to a compound for identifying alpha-synuclein aggregate and application thereof. The invention discloses a compound specifically combined with alpha-synuclein aggregate and a preparation method and application thereof. Specifically, the compound combined with the alpha-synuclein aggregate comprises a compound as shown in a formula A and a sub-general formula thereof, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a stable isotope variant of the compound. The compound disclosed by the invention is a small molecule tracer agent, and can specifically recognize alpha-synuclein aggregate; the compound can be used for preparing medicines for treating or diagnosing neurodegenerative diseases (such as Parkinson's disease, dementia with Lewy bodies, multisystem atrophy, Alzheimer's disease, amyotrophic lateral sclerosis, progressive suprakaryotic paralysis, progressive amyotrophy and the like) related to alpha-synuclein aggregates and other misfolded proteins.

The present invention discloses a biomarker for assisting in the diagnosis of progressive supranuclear palsy and its application, and relates to the field of biomedical technology. The biomarker is a neuron-derived extracellular vesicle carrying a tau deformed protein; the tau deformed protein is 4R tau or pTau181. The present invention has developed a biomarker that can assist in the diagnosis of progressive supranuclear palsy, which can effectively distinguish patients with progressive supranuclear palsy (PSP), Parkinson's disease (PD) and healthy people (HC). At the same time, a diagnostic model for progressive supranuclear palsy was also constructed, wherein the multivariate logistic regression model had a sensitivity of 95.7% for distinguishing between PSP and HC, a specificity of 90.0%, and an AUC of 0.974; the multivariate logistic regression model had a sensitivity of 96.3%, a specificity of 90.0%, and an AUC of 0.968 for distinguishing between PSP and PD.

The present invention provides methods for to sex-specific treatment and dose titration of diseases associated with an aberrant functionality of activity-dependent neuroprotective protein (ADNP) and / or cytoskeleton such as progressive supranuclear palsy (PSP), schizophrenia, amnestic mild cognitive impairment (aMCI), Alzheimer's disease, and autism. The treatment in these diseases, e.g., the dose and / or the regimen, differs between sexes and has to be adapted to obtain the desired effect. Specifically, use of davunetide in treatment of women suffering from PSP or of men suffering from schizophrenia or aMCI are provided.

The present invention relates to an agent for use in decreasing the level of intracellular phosphorylated tau in neurons, which agent can bind ELAVL4 with a binding affinity of at least - 8.0 kcal / mol. The agent comprises a structural element selected from the group consisting of a steroid backbone, a sugar moiety by glycosidic linkage, an O-linked glucuronide, and a lactone group and is suitably selected from the group of porphyrins, macrolactams, macrolides, vitamin D glucuronides, steroid glucuronides, withanolides, cardenolide glycosides, anthracyclines, ergoloid mesylates, ergotamines and derivates thereof, biphenyls, and piperazines. The administration of said agent leads to a decrease in protein levels of phosphorylated tau in normal neurons treated with the agent as compared to non-treated normal neurons and to a decrease in the Aβ42 / Aβ40 ratio in fAD neurons treated with the agent as compared to non-treated fAD neurons. The agent is administered for the treatment of a tauopathy, which may be involved in Alzheimer's disease, frontotemporal dementia, Parkinson's disease or progressive supranuclear palsy and multiple sclerosis.

Heterocyclic compounds of Formula I or Formula II or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof for imaging tau protein aggregates are provided. Compounds of Formula I or Formula II may be used to detect tau protein aggregates in the diagnosis or monitoring of the progression of a disease or disorder such as Alzheimer's disease, corticobasal degeneration and progressive suprakaryotic paralysis.

The invention relates to the technical field of treatment of neurodegenerative diseases, in particular to application of a DGAT1 specific oral inhibitor in neurodegenerative diseases, and the DGAT1 specific oral inhibitor is used for treating pathological tau protein related neurodegenerative diseases including Pick disease (PiD), Alzheimer's disease (AD), progressive suprakaryotic paralysis (PSP), cortical basal degeneration (CBD), silver granulopathy (AGD), familial tau proteopathy and the like. According to the application of the DGAT1 specific oral inhibitor in the treatment of the tau protein disease, the DGAT1 inhibitor is PF-04620110 (DGAT1 specificity) or PF-06865571 (DGAT1 and DGAT2 specificity). According to the application of the DGAT1 specific oral inhibitor in neurodegenerative diseases, the DGAT1 inhibitor can effectively penetrate through a blood-brain barrier through oral administration, the activity of a key enzyme DGAT1 for synthesizing triglyceride in glial cells is specifically inhibited, then abnormal accumulation of lipid droplets in the glial cells can be remarkably reduced through the targeted inhibition effect, and the DGAT1 specific oral inhibitor can be applied to neurodegenerative diseases. The normal physiological function is recovered.

Provided are RNAi agents, pharmaceutical compositions, and methods for reducing the amount or activity of PRNP RNA in a cell or a subject, and in certain instances reducing the amount of prion protein in a cell or a subject. Such RNAi agents, pharmaceutical compositions, and methods are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such neurodegenerative diseases include prion diseases, such as Creutzfeldt-Jakob disease (CJD) (e.g., variant Creutzfeldt-Jakob Disease (vCJD), classic Creutzfeldt-Jakob Disease (cCJD), familial Creutzfeldt-Jakob Disease (fCJD), or sporadic Creutzfeldt-Jakob Disease (sCJD)), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, or kuru; synucleinopathies such as Alzheimer's disease, Parkinson's disease, or dementia with Lewy bodies; or tauopathies such as frontal temporal dementia associated with a Tau mutation, Pick's disease, progressive supranuclear palsy, corticobasal neurodegeneration, or chronic traumatic encephalopathy (CTE).

The invention discloses a video product for inducing Parkinson's disease behaviors and a storage medium. The video product comprises three video clips, the first video clip displays target elements flickering at different positions, the second video clip displays the process that at least one moving element continuously moves along a set path, and the third video clip displays target elements and interference elements. The three video clips are used for respectively measuring the response ability, smooth tracking ability and attention ability of the subject to the rapidly changing visual stimulation. The subject is induced to make behavior feedback through various different elements in the video clip, and screening, diagnosis, treatment and curative effect evaluation of the Parkinson's disease, the multi-system atrophy and the progressive suprakaryotic paralysis are achieved according to the measurement result of the subject in the ability evaluation. By using the video product provided by the invention, the process objectivity of screening, diagnosis, treatment and curative effect evaluation is stronger, and the result has higher reliability and consistency.

Provided herein are artificial microRNA (miRNA) molecules for treating tauopathies. In some embodiments, the miRNA molecules target expression of Tau protein. Further provided herein are expression constructs, vectors (e.g., rAAV), cells, viral particles, and pharmaceutical compositions containing the artificial miRNA molecules. Yet further provided herein are methods and kits related to the use of the miRNA molecules, for example, to treat tauopathies including is Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia with parkinsonism-17, Pick's Disease, argyrophilic grain disease, globular glial tauopathy, chronic traumatic encephalopathy and post-encephalitic parkinsonism.

The present invention provides compositions and methods for inhibiting the autoimmune component of neurodegenerative diseases and thereby providing a therapeutic effect to patients suffering from such diseases. The compositions and methods comprise immunosuppressive moieties, such as regulatory T cells (Tregs) and proteins expressed by Tregs coupled to a chimeric antigen receptor or that specifically bind to one or more glial cell markers. Therapeutically effective doses of the compounds for treating neurodegenerative diseases, including progressive supranuclear palsy (PSP), Parkinson's disease (PD), Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), and prion diseases, are disclosed.

Provided herein are methods of administering ISIS 814907 for ameliorating Alzheimer's disease, reducing Tau RNA, or reducing Tau protein in a human subject in need thereof. In certain embodiments, the Alzheimer's disease is mild Alzheimer's disease, Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease, and / or Alzheimer's Disease Dementia (e.g., Mild Alzheimer's Disease Dementia). In certain instances, methods are useful for ameliorating at least one symptom or hallmark of a disease or disorder associated with Tau protein. In certain instances, the disease or disorder associated with Tau protein is a neurodegenerative disease or disorder. In certain instances, the disease or disorder associated with Tau protein is Alzheimer's disease or Fronto-temporal Dementia (FTD). In certain embodiments, the Alzheimer's disease is mild Alzheimer's disease, Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease, and / or Alzheimer's Disease Dementia (e.g., Mild Alzheimer's Disease Dementia). In certain instances, the disease or disorder associated with Tau protein is a tauopathy. In certain instances, the disease or disorder associated with Tau protein is Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular Glial Tauopathies, Epilepsy, and / or Dravet's Syndrome. Such symptoms or hallmarks include loss of memory, cognitive decline, loss of ability to understand or express speech, abnormal behavior, loss of and impaired motor function, or increase in the number and / or volume of neurofibrillary inclusions.