52 results about "Synucleinopathies" patented technology

The present invention relates to a gene therapy for treating synucleinopathies. The present invention provides a novel α-Syn peptide variant and inhibits the formation of amyloid fibrils and degrades α-Syn aggregates, thereby exhibiting excellent preventive, ameliorative, and therapeutic effects on synucleinopathies.

The invention relates to a method for detecting misfolded alpha-synuclein protein in a biological sample to determine the presence of synucleinopathies in an individual. The method provided by the present invention can also be used for differential diagnosis of Lewy fold synucleinopathies from MSA synucleinopathies as well as for monitoring of the disease progression in individuals. Moreover, a kit for detecting misfolded αSyn protein in biological samples is provided.

The disclosure provides peptide compositions and immunotherapy compositions comprising an amyloid-beta (Aβ, Abeta) peptide, a tau peptide, and an alpha-synuclein peptide. The disclosure also provides methods of treating or effecting prophylaxis of Alzheimer's disease or other diseases with beta-amyloid deposition in a subject, including methods of clearing deposits, inhibiting or reducing aggregation of Aβ and tau and an alpha-synuclein, blocking the uptake by neurons, clearing amyloid, and inhibiting propagation of tau seeds and an alpha-synuclein synucleinopathies in a subject having or at risk of developing Alzheimer's disease or other diseases containing tau and amyloid-beta and an alpha-synuclein accumulations. The methods include administering to such patients the compositions comprising an amyloid-beta (Aβ) peptide and a tau peptide and an alpha-synuclein peptide.

This invention provides libraries of Botulinum neurotoxin A (BoNT / A) protease variants for stepwise evolution of the enzyme to generate BoNT / A variants that can specifically cleave a desired cleavage site in a target protein. Related methods for performing stepwise evolution of BoNT / A with the BoNT / A variant libraries and simultaneous stepwise evolution of a desired substrate sequence in a target protein are also provided by the disclosure. Additionally provided in the disclosure are specifically evolved BoNT / A variant enzymes and conjugate proteins that specifically degrade intrinsically disordered proteins (IDPs) that are involved in human deceases, e.g., a-Synuclein. Polynucleotide sequences encoding the engineered BoNT / A proteases, expression vectors and related pharmaceutical compositions are also provided in this disclosure. Further encompassed by the invention are therapeutic methods that utilize the engineered BoNT / A enzymes in the treatment of various synucleinopathies.

Provided herein are postbiotic compositions prepared using successive fermentation methods of specific bacteria and plant fiber material. Also provided herein are methods, including for the treatment or prevention of the disruption of gut microbiota, or dysbiosis, associated with an antibiotic treatment, chemotherapy treatment, or administration of a dysbiosis-causing medications or medical treatments, using said postbiotic compositions, or for improving responses and / or reducing complications to treatments such as antibiotics or chemotherapy. Such postbiotic compositions can also be used for the treatment or prevention of the disruption of the gut-brain axis, including to treat or prevent neurological diseases or disorders, such as synucleinopathies, including but not limited to Parkinson's disease.

Methods of treating a subject with abnormal sleep associated with rapid eye movement (REM) sleep and slowing the progression of disease to synucleinopathies and Parkinson's disease by administering to the subject a formulation comprising an effective amount of piromelatine. Methods of treating a subject having abnormal sleep associated with rapid eye movement (REM) sleep and slowing the progression of abnormal sleep to chronic post-traumatic stress disorder (PTSD) by administering to the subject a formulation comprising an effective amount of piromelatine.

Provided herein are proteins comprising a monovalent human TfR binding domain ("human TfR binding proteins"), conjugates comprising such human TfR binding proteins, e.g., human TfR binding protein-dsRNA conjugates, pharmaceutical compositions comprising human TfR binding proteins or conjugates, and methods of using human TfR binding proteins or conjugates to treat CNS diseases, e.g., neurodegenerative diseases such as neurodegenerative synucleinopathies or tauopathies.

Provided herein are compounds, pharmaceutical compositions, and methods of use for reducing the amount or activity of SNCA mRNA in a cell or subject, and in some instances, the amount of alpha-synuclein in a cell or subject. Such compounds, pharmaceutical compositions, and methods of use are useful for ameliorating at least one symptom or marker of synucleinopathies. Such synucleinopathies include Parkinson's disease, Lewy body dementia (DLB), diffuse Lewy body disease, Parkinson's disease dementia (PDD), pure autonomic failure, multi-system atrophy (MSA), neurological Gaucher's disease, and Alzheimer's disease.

The invention provides antibodies that specifically bind human α-synuclein with a high affinity and reduces α-synuclein spreading in vivo, recombinant polypeptides comprising said antibodies or antigen-binding fragment thereof and methods for generating such polypeptides, as well as compositions and methods for generating α-synuclein antibodies, and methods of using α-synuclein antibodies for the treatment of diseases of the central nervous system, in particular alpha-synucleinopathies.

Alpha-Synuclein mutants and uses thereof are disclosed herein. The mutants of the present invention are non-self-aggregating forms of Alpha-Synuclein which make them a suitable candidate for use as substrates in aggregation assay for evaluating the presence of misfolded α-Syn protein. Also disclosed are kits and method for detection of synucleinopathies in individuals, using the mutants of the present invention.

The present invention relates to an isolated antibody, or antigen-binding portion thereof, with a higher binding affinity to alpha-synuclein oligomers compared to alpha-synuclein fibrils and / or alpha-synuclein monomers. The invention further describes in vitro and / or ex vivo methods using the isolated antibody, or antigen-binding portion thereof, to detect alpha-synuclein oligomers. The invention further provides a treatment-option for synucleinopathies, or provide a method to diagnose synucleinopathies.

The present invention relates to peptides, in particular of amyloid inhibitory peptides, and to pharmaceutical compositions comprising such peptides, for use in methods of treating or preventing or delaying the onset of synucleinopathies, in particular of Parkinson's disease (PD) or dementia with Lewy bodies, and their comorbidities, in particular PD / type 2 diabetes (T2D) and PD / Alzheimer's disease (AD). Furthermore, the present invention relates to such peptides, in particular such amyloid inhibitory peptides, for use in methods of diagnosing such synucleinopathies and related comorbidities. Furthermore, the present invention also relates to a kit for the in-vitro or in-vivo detection and, optionally, quantification of amyloidogenic polypeptides, amyloid fibrils or amyloid aggregates, and / or for the diagnosis of synucleinopathies and related comorbidities, in particular PD / type 2 diabetes (T2D) and PD / Alzheimer's disease (AD), in a patient.

Compositions and methods for treating one or more synucleinopathies or one or more TDP-43 proteinopathies or dementia with a compound of Formula (I), or pharmaceutically acceptable salts thereof, are provided. The compositions and methods may be used to improve one or more symptoms of one or more synucleinopathies or one or more TDP-43 proteinopathies. Formula (I): or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and ring A have any of the meanings herein defined in the description.

The application is directed to compounds of formulae (IA) and (IB) and their salts and solvates, wherein R1a, R2a, R3a, A1, A2, A3, R1b, R2b, R3b, B1, and B2 are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and / or prevention of, e.g., lysosomal storage diseases, such as Gaucher's disease, and α-synucleinopathies, such as Parkinson's disease.

Compositions and methods for treating one or more synucleinopathies or one or more TDP-43 proteinopathies or dementia with a compound of Formula (I), or pharmaceutically acceptable salts thereof, are provided. The compositions and methods may be used to improve one or more symptoms of one or more synucleinopathies or one or more TDP-43 proteinopathies. Formula (I):or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and ring A have any of the meanings herein defined in the description.

A composition for preventing or treating synucleinopathies, which includes efavirenz or a salt or solvate thereof and a pharmaceutically acceptable carrier, is provided. The composition is useful in preventing or treating synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, because the composition serves to hinder cell-to-cell transmission of alpha-synuclein, prevent intracellular aggregation of α-synuclein, and inhibit transmission of aggregated α-synuclein.

Disclosed are compounds of Formulas (I), (la), (lb), (II), (Ila), (III), (Illa), and (Illb), as well as pharmaceutical compositions thereof. The compounds can be used to improve proteostasis and enhance clearance of protein accumulation events by positively modulating the autophagy-lysosomal pathway, including augmenting the activity of cathepsin enzymes, and / or to treat neurological diseases, disorders and conditions, such as, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, frontotemporal dementia, amyotrophic lateral sclerosis, Lewy body dementias, chronic traumatic encephalopathy, traumatic brain injury, and α-synucleinopathies.

This disclosure pertains to combinations of immunogens or immunogenic compositions comprising a combination of immunogens consisting of i) a TQ immunogen comprising a cyclic compound consisting of α-syn peptide TKEQ (SEQ ID NO: 1) and a linker, and ii) a EK immunogen comprising a cyclic compound consisting of α-syn peptide EKTK (SEQ ID NO: 2) and a linker, and optionally iii) a further TQ immunogen comprising a cyclic compound consisting of α-syn peptide TKEQ (SEQ ID NO: 1) and a linker, alone or in combination with iv) a further EK immunogen comprising a cyclic compound consisting of α-syn peptide EKTK (SEQ ID NO: 2) and a linker, and to uses and methods of administration of the combinations or compositions.

The present invention relates to antibodies binding alpha synuclein and fragments thereof capable of binding alpha synuclein as a monomer and in fibrils and preventing alpha synuclein aggregation induced by alpha synuclein fibrils. The antibodies of the present invention are for use in the treatment of alpha synucleinopathies, including Parkinson's disease.

Provided herein are artificial microRNA (miRNA) molecules for treating synucleinopathies. In some embodiments, these miRNA molecules target the expression of SNCA protein. Further provided herein are expression constructs, vectors (e.g., rAAV), cells, viral particles, and pharmaceutical compositions containing these artificial miRNA molecules. Still further provided herein are methods and kits related to the use of these miRNA molecules, e.g., for treating synucleinopathies including Parkinson’s disease, multiple system atrophy, or Lewy body dementia.

The present disclosure relates to methods of preventing, or delaying the progression of, death of neurons and / or microgliosis and / or astrogliosis that contributes to the death of neurons. The present disclosure also relates to methods of treating, preventing, or delaying the progression of, a synucleinopathy (e.g., Parkinson's disease). Also disclosed are related in vitro, ex vivo, and in vivo methods of identifying agents and / or compositions useful for preventing, or delaying the progression of, death of neurons and / or microgliosis and / or astrogliosis that contributes to the death of neurons and agents and / or compositions useful for treating, preventing, or delaying the progression of, a synucleinopathy. The agents and / or compositions of the present disclosure decrease the level and / or activity of a cis-regulatory element that propagates the misfolding and aggregation of proteins encoded by synucleinopathy-associated genes in neurons and / or glial cells.

The present invention relates to extracellular vesicles (EVs) derived from human dendritic cells (hDCs) comprising a RVG-hLAMP peptide construct, having sequence SEQ ID NO. 1, expressed on the surface thereof, wherein the extracellular vesicles are loaded with anti-α-synuclein shRNA minicircles (ShRNA-MCs). Likewise, the invention relates to the clinical use of said vesicles in the treatment of synucleinopathies. Lastly, the present invention relates to a method for producing the extracellular vesicles from human dendritic cells (hDCs).

Disclosed are compounds of Formulas (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), and (IIIb), as well as pharmaceutical compositions thereof. The compounds can be used to improve proteostasis and enhance clearance of protein accumulation events by positively modulating the autophagy-lysosomal pathway, including augmenting the activity of cathepsin enzymes, and / or to treat neurological diseases, disorders and conditions, such as, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, mild cognitive impairment, frontotemporal dementia, amyotrophic lateral sclerosis, Lewy body dementias, chronic traumatic encephalopathy, traumatic brain injury, and α-synucleinopathies.

Provided are antisense agents, pharmaceutical compositions, and methods of use for reducing the amount or activity of alpha-synuclein (SNCA) RNA in a cell or subject, and in certain instances reducing the amount of alpha-synuclein protein in a cell or subject. In certain embodiments, also provided herein are oligomeric compounds, oligomeric duplexes, and RNAi agents for reducing the amount or activity of SNCA RNA in a cell or subject, and in certain instances reducing the amount of SNCA protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such neurodegenerative diseases include synucleinopathies, e.g., Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, Parkinson's disease dementia, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher's disease, and Alzheimer's disease.

The present invention relates to agents, uses and methods for the treatment of synucleinopathies, in particular to novel monoclonal anti-alpha-synuclein antibodies. These antibodies can be used to treat synucleinopathies, such as Parkinson's disease, including idiopathic and genetic forms of Parkinson's disease, diffuse Lewy body disease (DLBD), Lewy body variants of Alzheimer's disease (LBV), combinatorial Alzheimer's and Parkinson's disease, pure autonomic failure, and multi-system atrophy.

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 current invention relates to QPCTL inhibitors represented by formula (I), and corresponding compositions and uses. Preferably, the inhibitors and compositions are for use in the treatment of cancer, neurodegenerative diseases such as Alzheimer's disease, synucleinopathies, Huntington's disease, bacterial infections such as periodontitis and related disorders, and inflammatory diseases.

Provided herein are pharmaceutical compositions and methods for treatment or prevention of synucleinopathies with small-molecule inhibitors of pathogenic α-synuclein activity having the Formula (I). Also, provide are methods for identifying novel compounds for modulating α-synuclein activity.

The present invention relates to novel monoclonal anti-alpha-synuclein antibodies. These antibodies can be used to treat synucleinopathies, such as Parkinson's disease (including idiopathic and genetic forms of Parkinson's disease), diffuse Lewy body disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), combined Alzheimer's and Parkinson's disease, pure autonomic failure, and multiple system atrophy.

The present disclosure provides methods, compounds, compositions, formulations, or medicaments for treating, preventing, inhibiting, ameliorating, or delaying the onset of a- synucleinopathies (e.g., Parkinson's disease (PD), PD with dementia (PDD), dementia with Lewy bodies (LBD), or Multiple System Atrophy (MSA)) as well as methods for ameliorating, inhibiting, or delaying the onset of signs or symptoms of an a-synucleinopathy in a subject. The disclosed methods, compounds, compositions, formulations, or medicaments are also useful for addressing the related signs and symptoms of a- synucleinopathies. The methods comprise administering to the subject the compounds, mixtures of compounds, or compositions, formulations, or medicaments derived from said compounds or mixtures thereof to thereby produce the aforementioned therapeutically beneficial effect(s).