28 results about "Supranuclear palsy" patented technology

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.

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).

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

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.

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 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.

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 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.

To provide CAR-Treg-based therapies for treating neurodegenerative diseases.SOLUTION: The invention provides compositions and methods for suppressing autoimmune components of neurodegenerative diseases, thereby providing therapeutic effects to patients suffering from such diseases. Compositions and methods include immunosuppressive moieties such as regulatory T cells (Tregs) and proteins expressed by Tregs coupled to a chimeric antigen receptor or protein that specifically binds 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.SELECTED DRAWING: None

To provide a method for collecting data to evaluate the probability that a subject is afflicted with progressive supranuclear palsy.SOLUTION: The present invention provides a method that includes, in a subject-derived cerebrospinal fluid sample, measuring the amount of a first type of molecules that are bound with an antibody recognizing the KEGILQYCQEVYPELQ epitope in amyloid precursor protein and have an apparent molecular mass of 100 kDa, where the measurement data on the first type of molecules is collected as data with a positive correlation with the probability that a subject is afflicted with progressive supranuclear palsy.SELECTED DRAWING: Figure 3

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.

To provide a biomarker correlating with the presence of progressive supranuclear palsy (PSP).SOLUTION: A method for collecting data for evaluating whether a subject may suffer from progressive supranuclear palsy, the method comprising measuring an amount of miR-6088 in a biological sample derived from the subject, the amount being collected as data that positively correlates with the possibility that the subject suffers from progressive supranuclear palsy.SELECTED DRAWING: Figure 1

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 proteins 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.

The present invention is directed to activators of TMEM175 Ion Channel, which are compounds of Formulae: (AAA), (AA), (A), (I), (II), (III), (IV), (V), (VI), (B), (B-I), and (B-II). The activators described herein can be useful in the treatment of diseases or disorders associated with disfunction of TMEM175 Ion Channel, such as Neurological Disorders, Parkinson's Disease, Alzheimer's disease, dementia with Lewy bodies (DEB), multisystem atrophy (MSA), progressive supranuclear palsy (PSP). In particular, the invention is concerned with compounds and pharmaceutical compositions activating TMEM175 Ion Channel in a cell, methods of treating diseases or disorders associated with disfunction of TMEM175 Ion Channel, and methods of synthesizing these compounds.

The present invention relates to the field of biomedical technology and discloses the use of astrocyte-derived extracellular vesicles (EVs) carrying Tau in the aided diagnosis of progressive supranuclear palsy (PSP). Using fluorescently labeled antibodies specific to Tau protein and anti-glutamate transporter 1 antibodies, the present invention accurately detects Tau-carrying EVs from astrocytes in plasma. By analyzing the concentration of Tau-carrying EVs in plasma, the present invention accurately differentiates patients with PSP from those with Parkinson's disease (PD) and healthy individuals. This provides a highly effective diagnostic biomarker and model for PSP, offering new empirical methods and technical support for the diagnosis and differentiation of PSP.