87 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 provides improved and minimally invasive biomarker-based diagnostics for synucleinopathies (e.g., Parkinson's disease (PD)). The invention further provides assays and methods for analysis of biological samples, for the evaluation and determination of characteristics pertaining to pathological processes associated with α-synuclein, and to methods for determining the suitability of analytical agents for diagnosis of synucleinopathies. More specifically, the invention in embodiments thereof provides improved methods comprising specific detection and quantification of α-synuclein-based biomarkers from low volumes of biological samples.

To provide novel monoclonal anti-α-synuclein antibodies.SOLUTION: Disclosed is an antibody that can bind to the toxic α-synuclein fragment 1 to 119 / 122 and neutralize this truncated form of α-synuclein. The antibody can be used to treat synucleinopathies such as Parkinson's disease (including idiopathic and hereditary Parkinson's disease), diffuse Lewy body disease (DLBD), Lewy body variant Alzheimer's disease (LBV), combined Alzheimer's and Parkinson's disease, pure autonomic failure, and multiple system atrophy.SELECTED DRAWING: None

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a SNCA gene, particularly in a CNS tissue, as well as methods of inhibiting expression of a SNCA gene and methods of treating subjects having a SNCA-associated neurodegenerative disease or disorder, e.g., Parkinson's Disease (PD), multiple system atrophy (MSA), Lewy body dementia (LBD), among other synucleinopathies, using such dsRNAi agents and compositions.

The present disclosure is directed to single domain antibodies that bind to α-synuclein and the use of these antibodies for the treatment and diagnosis of α-synucleinopathies. The present disclosure is also directed to polynucleotides encoding the α-synuclein single domain antibodies, therapeutic vectors comprising these polynucleotides and methods of administering these therapeutic vectors for the treatment of α-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 disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting a SNCA gene, particularly in a CNS tissue, as well as methods of inhibiting expression of a SNCA gene and methods of treating subjects having a SNCA-associated neurodegenerative disease or disorder, e.g., Parkinson's Disease (PD), multiple system atrophy (MSA), Lewy body dementia (LBD), among other synucleinopathies, using such dsRNAi agents and compositions.

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.

A method of detecting the presence of alpha-synuclein aggregation in a biological sample is provided whereby a biological sample is mixed with a reaction sample comprising a population of beads, a fluorophore adapted to bind to protein aggregates and to increase fluorescence when bound to protein aggregates, and alpha-synuclein or a fragment or variant thereof to form a reaction mixture, wherein a significant increase in the fluorescence of the reaction mixture during incubation is indicative of the presence of aggregates of alpha-synuclein in the biological sample.

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.

The present invention describes the use of a NK1-antagonist, in combination with 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine, to facilitate the treatment of a patient suffering from a synucleinopathy by enabling a therapeutically effective 6-propylamino-4,5,6,7-tetrahydro-1,3-benzothiazole-2-amine daily dose to act without the typical adverse effects caused by pramipexole dihydrochloride monohydrate when administered alone.

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.

The invention relates to an application of a substance for detecting high signals of dorsal-lateral nigra in preparation of a product for detecting alpha-synucleinopathies. The Parkinson's disease and rapid eye movement sleep behavior disorder diagnosis system is constructed based on an analysis strategy of magnetic sensitive weighted imaging, the diagnosis system can be effectively applied to auxiliary diagnosis, the diagnosis sensitivity of the Parkinson's disease is 93.8%, the specificity is 96.7%, the diagnosis sensitivity of the rapid eye movement sleep behavior disorder is 66.7%, and the diagnosis sensitivity of the rapid eye movement sleep behavior disorder is 96.7%. The kit has the advantages that the sensitivity is high, the specificity is 98.0%, the rapid eye movement sleep behavior disorder or the Parkinson's disease can be subjected to etiological typing, systematic management and effective prevention of patients are facilitated, the clinical diagnosis uncertainty of the Parkinson's disease is remarkably reduced through the diagnosis mode, early screening diagnosis is promoted, and the clinical diagnosis and treatment level is improved.

The present disclosure relates to a bispecific antibody that specifically binds to alpha-synuclein and IGF1R, and an use of the bispecific antibody for the prevention, treatment and / or diagnosis of synucleinopathies associated with alpha-synuclein or alpha-synuclein aggregates, and can allow the alpha-synuclein antibody or an antigen-binding fragment thereof to penetrate the blood brain barrier to exert its action in the brain, and extend the half-life to maintain the efficacy for a long time.

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 disclosure provides isolated binding proteins such as humanized antibodies and antigen-binding fragments thereof that target alpha-synuclein, including multispecific isolated binding proteins that target both alpha-synuclein and insulin-like growth factor 1 receptor. Also provided are methods of using the binding proteins to treat alpha-synucleinopathies.

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.

There is provided a compound of formula I for use in a method for treating or preventing a synucleinopathy disease, the method comprising administering to a subject, a therapeutically effective amount of said compound (I): or a pharmaceutically acceptable salt or hydrate thereof.