70 results about "Synucleinopathies" patented technology

The present application relates to single-stranded or double-stranded interfering RNA molecules (e.g., siRNAs) that target the alpha synuclein (SNCA) gene. The interfering RNA molecule may contain a specific pattern of nucleoside modification and inter-nucleoside linkage modification as a pharmaceutical composition comprising the interfering RNA molecule. The siRNA molecule may be a branched siRNA molecule, such as a two-branched, three-branched or four-branched siRNA molecule. The disclosed siRNA molecules may also be characterized by a 5 '-phosphorus stabilizing moiety and / or a hydrophobic moiety. In addition, the present disclosure provides methods for delivering siRNA molecules of the present disclosure to a subject, such as the central nervous system of a subject identified as having synucleinopathies.

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.

Disclosed are new small molecules having a substituted pyrimidine or substituted fused pyrimidine core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including Gaucher's disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.

The present disclosure provides compounds, compositions and methods useful for the treatment of neurodegenerative diseases, in particular synucleinopathies.

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.

The present invention provides new inhibitors of LRRK2 / PP1 interaction able to pass through the Blain Blood Barrier and to target the brain. The present invention relates to these inhibitors for use as medicament and more particularly to methods and pharmaceutical compositions for the treatment of neurodegenerative disorders, more particularly α-synucleinopathies.

The present invention relates to stable and low viscosity liquid pharmaceutical compositions comprising antibodies binding to human alpha synuclein and to methods for use of antibodies binding to human alpha synuclein for treating synucleinopathies or prodromal synucleinopathy, incl. suitable doses and / or dosing regimens. These antibodies for use in treatment of synucleinopathies or prodromal synucleinopathy may be formulated in the stable and low viscosity liquid pharmaceutical compositions of the invention.

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.

Provided herein are artificial microRNA (miRNA) molecules for treating synucleinopathies. In some embodiments, the miRNA molecules target expression of SNCA 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 synucleinopathies including Parkinson's Disease, Multiple System Atrophy, or Dementia with Lewy Bodies.

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.

The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which is useful as a drug. In addition, the present invention provides a pharmaceutical composition for treating or preventing synucleinopathies.

The present invention relates to stable and low viscosity liquid pharmaceutical compositions comprising antibodies binding to human alpha synuclein and to methods for use of antibodies binding to human alpha synuclein for treating synucleinopathies or prodromal synucleinopathy, incl. suitable doses and / or dosing regimens. These antibodies for use in treatment of synucleinopathies or prodromal synucleinopathy may be formulated in the stable and low viscosity liquid pharmaceutical compositions of the invention.

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.

The present invention relates to stable and low viscosity liquid pharmaceutical compositions comprising antibodies binding to human alpha synuclein and to methods for use of antibodies binding to human alpha synuclein for treating synucleinopathies or prodromal synucleinopathy, incl. suitable doses and / or dosing regimens. These antibodies for use in treatment of synucleinopathies or prodromal synucleinopathy may be formulated in the stable and low viscosity liquid pharmaceutical compositions of the invention.

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.

A method of detecting alpha-synuclein in a sample of a subject as well as assays, methods and treatments of alpha-synucleinopathies are disclosed. The method of the alpha-synuclein comprises the steps of: a) obtaining a sample from a subject; 5b) using the sample for a luminescence assay; and c) optionally comparing the result to a control.