56 results about "Cerebroside" patented technology

The disclosure relates to compositions and methods for, inter alia, altering, e.g., enhancing, the level of GBA1 protein via delivery using an adeno-associated viral (AAV) capsid variant. The compositions and methods of the present disclosure are useful, inter alia, for the treatment of subjects who have, have been diagnosed with having, or are at risk of having a GBA1-related disorder, e.g., Parkinson's Disease (PD), Gaucher Disease (GD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), or Lewy Body Dementia (LBD).

Provided are a compound having a 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof, of Formula 1a pharmaceutical composition comprising the same and a use thereof, where the compound having a 1,2,3,4-tetrahydronaphthalene moiety or pharmaceutically acceptable salt thereof has an inhibitory activity against glucosylceramide synthase (GCS), and therefore can be usefully applied for preventing or treating various diseases associated with GCS, such as Gaucher disease, Fabry disease, Tay-Sachs disease, Parkinson's disease, etc.

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. Applicants engineered an AAV capsid, BI-hTFRl, that binds human Transferrin Receptor (TfRl), a protein expressed on the blood-brain barrier (BBB). BI-hTFRl was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFRl substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9.

A genetically modified human beta-glucocerebrosidase (GCase) is disclosed. The genetically modified GCase comprises an amino acid sequence at least 85% identical to SEQ ID NO:2; contains mutations at positions L34P, K224N / G, T369E, and N370D corresponding to SEQ ID NO:2; and is capable of catalyzing the hydrolysis of the glycolipid glucosylceramide (GlcCer). Pharmaceutical compositions comprising the genetically modified GCase and therapeutic methods using the same are also disclosed.

This application relates to polypeptide agents and compositions specifically binding human beta-glucocerebrosidase (GCase, GBA1). Particularly, immunoglobulin single variable domains (ISVDs) are described which allosterically bind human GCase, thereby positively modulating GCase in its stability and / or catalytic activity. The invention relates further to vectors and nucleic acids encoding such ISVD-based modulators. Also encompassed are compositions, in particular pharmaceutical compositions, containing such ISVD modulators. The GCase-specific allosteric modulators, specifically the ISVDs and compositions described herein, may be used for prevention and / or treatment of GCase-related diseases, including Gaucher disease (GD) and Parkinson's disease (PD).

There is provided a recombinant adeno-associated virus (rAAV) vector comprising one or both of (a) to (c): (a) a nucleotide sequence encoding an aromatic L-amino acid decarboxylase (AADC); (b) a nucleotide sequence for encoding glucocerebrosidase (GBA1); and (c) a nucleotide sequence encoding a neurotrophic factor (NTF), such as brain dopamine neurotrophic factor (CDNF) or glial cell-derived neurotrophic factor (GDNF), for use in the treatment of neurodegenerative disorders, in particular Parkinson's disease (PD), Multi-System Atrophy (MSA), Gaucher's disease (GD) and other proteinopathies. Also provided herein are viral particles comprising the rAAV vector, pharmaceutical compositions comprising the viral particles, and uses thereof.

Provided is a recombinant adeno-associated viral (rAAV) vector comprising one or two of (a) to (c): (a) a nucleotide sequence encoding aromatic L-amino acid decarboxylase (AADC), (b) a nucleotide sequence encoding glucocerebrosidase (GBA1); and (c) a nucleotide sequence encoding a neurotrophic factor (NTF), such as cerebral dopamine neurotrophic factor (CDNF) or glial cell derived neurotrophic factor (GDNF), for treating neurodegenerative disorders, particularly Parkinson's disease (PD), Multiple system atrophy (MSA), Gaucher's disease (GD), and other proteinopathies. Also provided herein are viral particles comprising the rAAV vector, a pharmaceutical composition comprising the viral particles, and uses thereof.

The disclosure relates, in some aspects, to compositions and methods for treatment of diseases associated with aberrant lysosomal function, for example Parkinson's disease and Gaucher disease. In some embodiments, the disclosure provides expression constructs comprising a transgene encoding beta-Glucocerebrosidase (GBA) or a portion thereof, Lysosomal Membrane Protein 2 (LIMP2), Prosaposin, or any combination of the foregoing. In some embodiments, the disclosure provides methods of Parkinson's disease by administering such expression constructs to a subject in need thereof.

Provided are compounds represented by formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing same, and the use thereof as a β-glucocerebrosidase (GCase) allosteric modulator, preferably for treating neurodegenerative diseases.

Provided herein are compounds that modulate glucocerebrosidase (GCase), an enzyme whose activity is associated with neurological diseases and disorders (e.g., Gaucher's disease, Parkinson's disease). Also provided are pharmaceutical compositions and kits comprising the compounds, and methods of treating GCase-related diseases and disorders (e.g., Gaucher's disease, Parkinson's disease) with the compounds in a subject, by administering the compounds and / or compositions described herein.

Provided are recombinant adeno-associated virus (rAAV) vectors comprising one or two of (a) to (c): (a) a nucleotide sequence encoding an aromatic L-amino acid decarboxylase (AADC); (b) a nucleotide sequence encoding a glucocerebrosidase (GBA1); and (c) a nucleotide sequence encoding a neurotrophic factor (NTF) such as a brain dopamine neurotrophic factor (CDNF) or a glial cell-derived neurotrophic factor (GDNF), for use in the treatment of neurodegenerative disorders, in particular Parkinson’s disease (PD), multiple system atrophy (MSA), Gaucher’s disease (GD), and other proteinopathies. Also provided herein are viral particles comprising the rAAV vectors, pharmaceutical compositions comprising the viral particles, and uses thereof.

A persistent encapsulation structure capable of preventing the degradation of bioactive substances, which encapsulation structure comprises a variety of encapsulation structure bodies (10), characterized by that the respective encapsulation structure body (10) has a polysaccharide structure (11) by which a plurality of bioactive substances (12) are encapsulated, wherein the bioactive substance (12) is selected from a group consisting of a bioactive fatty substance (121) and a bioactive non-fatty substance (122); that the polysaccharide structure (11) comprises at least one polysaccharide, wherein the at least one polysaccharide is first thoroughly mixed, then sheared at high pressure or homogenized at high speed and finally atomized dried, such that the polysaccharide structure (11) forms branched polysaccharides and linear polysaccharides which form a multitude of network structures; that the bioactive fatty substance (121) is selected from a group consisting of glycerophospholipids, sphingophospholipids, gangliosides, L-α- / glycerylphosphorylcholines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol, phosphatidylserines, phosphatidic acids, phosphatidylglycerol, ceramides, glucocerebrosides, glycolipids, cholesterols and fatty acid substances; and that the bioactive nonfatty substance (122) is selected from a group of coenzymes, vitamins, carotenes, carotenoids, curcuminoids, curcumin, curcumin extract, polyphenols, saponins, glycosides, terpenoids, ergothioneine, minerals, acid substances, functional polysaccharides, carbohydrates, functional proteins, peptides, amino acids and their derivatives.

Provided herein is a method of treating or preventing or diagnosing a central nervous system central nervous system disease, disorder, trauma or injury. The method comprises use of a lipid nanoparticle comprising at least one nucleic acid encoding an antibody or antigen-binding fragment and the lysosomal enzyme glucocerebrosidase. Also provided is a lipid nanoparticle that can be used with the method disclosed herein.

The present disclosure is generally directed GCase polypeptides and fragments thereof as well as fusion proteins and complexes comprising a GCase polypeptide or fragment thereof and an antigen-binding domain that specifically binds to human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc). Such fusion proteins and complexes can transport the GCase polypeptide or fragment thereof across the blood-brain barrier (BBB), e.g., for treatment of GCase deficiencies in the central nervous system.

The present application belongs to the field of medicine, and particularly relates to a class of cerebrosides and the use of the pharmaceutical composition thereof as an immunosuppressive agent in the preparation of a medicine for preventing or treating immune-related diseases.

This invention belongs to the field of exosome preservation technology and discloses a stabilizer composition for exosome cryopreservation and its application. The stabilizer composition for exosome cryopreservation provided by this invention consists of the following components and their amounts: phytosphingosine: 0.1%-0.2%; cerebroside sulfate: 0.05%-0.1%; trehalose: 2%-5%; lipid-soluble antioxidant: 0.01%-0.05%; HEPES buffer: 10-20 mM; metal ion chelating agent: 0.01%-0.05%. The composition of this invention forms a "gradient protection" through the membrane insertion of phytosphingosine and the shallow negative charge shielding of cerebroside sulfate, enabling stable cryopreservation of exosomes for more than one week with a bioactivity retention of >85%. This preservative is animal-free, easy to use, and effective, making it suitable for the clinical translation and practical application of exosomes.

Provided are recombinant adeno-associated virus (rAAV) vectors comprising one or two of (a) to (c): (a) a nucleotide sequence encoding an aromatic L-amino acid decarboxylase (AADC); (b) a nucleotide sequence encoding a glucocerebrosidase (GBA1); and (c) a nucleotide sequence encoding a neurotrophic factor (NTF) such as a brain dopamine neurotrophic factor (CDNF) or a glial cell-derived neurotrophic factor (GDNF), for use in the treatment of neurodegenerative disorders, in particular Parkinson’s disease (PD), multiple system atrophy (MSA), Gaucher’s disease (GD), and other proteinopathies. Also provided herein are viral particles comprising the rAAV vectors, pharmaceutical compositions comprising the viral particles, and uses thereof.

The present disclosure provides engineered glucocerebrosidase enzymes, polynucleotides encoding the engineered glucocerebrosidase enzymes, and methods of using the engineered glucocerebrosidase enzymes or the recombinant polynucleotides encoding the engineered glucocerebrosidase enzymes to treat a lack of glucocerebrosidase activity.

The present disclosure is generally directed GCase polypeptides as well as fusion proteins and complexes comprising a GCase polypeptide and an antigen-binding domain that specifically binds to blood-brain barrier (BBB) target such as human transferrin receptor (TfR) or human CD98 heavy chain (CD98hc). Such fusion proteins and complexes can transport the GCase polypeptide across BBB, e.g. for treatment of GCase deficiencies in the central nervous system.

The present invention relates to modified β-glucocerebrosidase (GCase) polypeptides and polynucleotides comprising modified glucocerebrosidase (GBA) nucleotide sequences. The present invention further relates to viral particles comprising recombinant genomes comprising polynucleotides of the invention, and compositions comprising modified GCase polypeptides, polynucleotides, or viral particles of the invention. The present invention also relates to methods and uses of the modified GCase polypeptides, polynucleotides, viral particles, and / or compositions of the invention. The present invention further relates to modified GCase polypeptides, polynucleotides, viral particles, or compositions of the invention for use in a method of treatment or for use in the manufacture of a medicament for use in a method of treatment.

The present invention relates to the use of an active pharmaceutical ingredient N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-methylenimine acyl chloride and an acid addition salt thereof in the preparation of an oral medicament for the treatment of glucocerebrosidase (GBA)-related Parkinson's disease or GBA-related Parkinson's syndrome. The invention also relates to the use of the N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-methylenimine acyl chloride and the acid addition salt thereof.

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.

A nucleic acid fragment comprising a nucleotide sequence encoding a human glucocerebrosidase (GCase) is provided. The invention also provides an expression vector containing the nucleic acid fragment, a recombinant adeno-associated virus (rAAV) containing the expression vector, a pharmaceutical composition containing the nucleic acid fragment, the expression vector or the rAAV, and application of the nucleic acid fragment, the expression vector or the rAAV in treatment of central nervous system diseases.

The present invention relates to recombinant DNA molecule encoding β-glucocerebrosidase (GCase) enzyme. The present invention also relates to recombinant DNA construct, recombinant vector, recombinant host cell, mRNA molecule, delivery system, pharmaceutical compositions and method of treating or managing symptoms of Gaucher disease in a subject.

The application provides compounds of Formula (I), and their salts and solvates, wherein A1, A2, A3, A4, R1, R2, R3, R4, R5, R6, R7, R8, m, and n are defined as set forth in the specification, and their use in the treatment and / or prevention of diseases and conditions associated with the alteration of the activity of β-glucocerebrosidase.

A genetically modified human beta-glucocerebrosidase (GCase) is disclosed. The genetically modified GCase comprising an amino acid sequence at least 85 % identical to SEQ ID NO: 2; and comprising mutations at coordinates L34P, K224N / G, T369E and N370D, where the coordinates correspond to said SEQ ID NO: 2; and capable of catalyzing hydrolysis of a glycolipid glucosylceramide (GlcCer). Pharmaceutical compositions comprising the genetically modified GCase and therapeutic methods of using same are also disclosed.

FIELD: neurology; laboratory diagnostics.SUBSTANCE: used for the differential diagnosis of Parkinson's disease not associated with mutations in the GBA1 gene, and multiple system atrophy. The patient's peripheral venous blood is collected, from which mononuclear cells are isolated by gradient centrifugation, followed by their differentiation into a primary culture of macrophages in the presence of the macrophage colony-stimulating growth factor M-CSF to ensure proliferation and differentiation of monocytes into mature macrophages. The obtained blood macrophage cells are applied to 903 filter cards at a concentration of 2×106 cells / ml. Whatman 903 Sample Collection Cards can be used as 903 filter cards. The activity of lysosomal enzymes is determined: glucocerebrosidase GCase, alpha-galactosidase GLA, acid sphingomyelinase ASMase, galactosylceramidase GALC by high-performance liquid chromatography in combination with tandem mass spectrometry. The value of the canonical linear discriminant function CLDF is calculated using the stated formula. If the value of CLDF is ≥ 43.44, the patient is diagnosed with multiple system atrophy. If the value of CLDF is < 43.44, Parkinson's disease is diagnosed in patients who do not have a mutation in the GBA1 gene.EFFECT: method enables reliable and accurate differential diagnosis of Parkinson's disease and multiple system atrophy by assessing the activity of lysosomal enzymes.2 cl, 2 dwg, 2 ex

Provided are methods for preventing, limiting, or delaying clinical motor progression in a subject suffering from Parkinson's disease carrying low GCase activity, such as a PD (GBA-PD) patient carrying a pathogenic variation of the glucocerebrosidase 1 (GBA1) gene, comprising administering to the subject a therapeutically effective amount of 5, 7-dimethyl-N-((1R, 4R)-4-(pentyloxy) cyclohexyl) pyrazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, the present invention relates to a pharmaceutically acceptable salt of pyrimidine-3-carboxamide (compound A) or a pharmaceutically acceptable salt thereof.