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WO2020197367A1 - Composition pour la prévention ou le traitement du diabète à l'aide de st8sia1, et procédé de criblage d'agents antidiabétiques - Google Patents

Composition pour la prévention ou le traitement du diabète à l'aide de st8sia1, et procédé de criblage d'agents antidiabétiques Download PDF

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WO2020197367A1
WO2020197367A1 PCT/KR2020/095049 KR2020095049W WO2020197367A1 WO 2020197367 A1 WO2020197367 A1 WO 2020197367A1 KR 2020095049 W KR2020095049 W KR 2020095049W WO 2020197367 A1 WO2020197367 A1 WO 2020197367A1
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st8sia1
cells
protein
diabetes
composition
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Korean (ko)
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황인후
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Hwang Jung Hoo
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Hwang Jung Hoo
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • A61K35/545—Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0676—Pancreatic cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a composition for preventing or treating diabetes using ST8SIA1 and a method for screening a diabetes therapeutic agent, and more particularly, to a diabetes mellitus comprising as an active ingredient an inhibitor of the expression or activity of the ST8SIA1 protein or insulin-secreting cells in which the ST8SIA1 gene is deleted.
  • Glucose toxicity in diabetes causes apoptosis of ⁇ -cells and affects various organ systems, including the pancreas.
  • the basic mechanism is not fully known. Impairment of ⁇ -cells and impaired insulin production are typical features of diabetes (Xu, G et al., Nat. Med. 19, 1141-1146. 2013), but apoptosis of ⁇ -cells is prevented despite the rapid spread of diabetes. The exact molecular mechanism of the resulting glucose toxicity is still unknown (Chen, J et al., Diabetes 57, 938-944. 2008).
  • Apoptosis is a process that naturally occurs in the body by activating specialized intracellular signal transduction to destroy cells. It is also a homeostatic mechanism for maintaining cell populations in tissues. Inadequate apoptosis is fundamentally common in a variety of pathologies, including metabolic stress such as ischemic injury, autoimmune diseases and many types of cancer, neurodegenerative diseases, and glucose toxicity (Elmore, S et al., Toxicol. Pathol. 35, 495-516. 2007).
  • Such apoptosis is caused by intrinsic pathways that activate caspase-9 and -3 by cytochrome c released from mitochondria, and caspase-8 and -10 by death receptors such as TNF- ⁇ (tumor nerosis factor- ⁇ ) and Fas ligand. This activation is divided into two pathways of the extrinsic pathway. In addition, it is known that activation of various proteins independent of caspase is involved in apoptosis signaling.
  • the ST8SIA1 gene is a gene that encodes an enzyme called alpha-N-acetyl neuraminide alpha-2,8-sialyl transferase, and the enzyme transfers sialic acid from CMP-sialic acid to GM3 to ganglioside ( Ganglioside) is a type II membrane protein that produces GD3 and GT3. Ganglioside GD3 is known to be important for cell adhesion and growth of cultured malignant cells.
  • the ST8SIA1 protein can often be found in the Golgi apparatus and is a member of the glycosyltransferase family.
  • ST8SIA1 can act as a target of diabetes treatment as in the present invention.
  • ST8SIA1 has a function of inhibiting apoptosis of pancreatic beta cells, particularly in a high glucose state caused by diabetes, and inhibiting this.
  • the present invention was completed by confirming that the amount of insulin secreted in the body is increased by the insulin secreting cells and that blood sugar is normally regulated.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes, comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • compositions for preventing or treating diabetes comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • compositions for preventing or treating diabetes consisting essentially of an inhibitor of the expression or activity of the ST8SIA1 protein as an active ingredient.
  • Another object of the present invention is to provide a third object of the present invention.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diabetes, comprising as an active ingredient insulin secreting cells in which the ST8SIA1 gene is deleted.
  • compositions for preventing or treating diabetes comprising the insulin-secreting cells in which the ST8SIA1 gene is deleted as an active ingredient.
  • compositions for preventing or treating diabetes consisting essentially of insulin-secreting cells in which the ST8SIA1 gene is deleted as an active ingredient.
  • Another object of the present invention is to provide the use of an inhibitor of the expression or activity of the ST8SIA1 protein for preparing a preparation for preventing or treating diabetes.
  • Another object of the present invention is to provide a method for treating diabetes, comprising administering to an individual in need thereof an effective amount of a composition comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes consisting essentially of an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising as an active ingredient insulin secreting cells in which the ST8SIA1 gene is deleted.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising insulin-secreting cells in which the ST8SIA1 gene is deleted as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes consisting essentially of insulin-secreting cells in which the ST8SIA1 gene is deleted as an active ingredient.
  • the present invention provides a use of an inhibitor of the expression or activity of the ST8SIA1 protein for preparing a preparation for preventing or treating diabetes.
  • the present invention provides a method for treating diabetes comprising administering to an individual in need thereof an effective amount of a composition comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating diabetes, comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • treatment refers to suppression of occurrence or recurrence of a disease, alleviation of symptoms, reduction of direct or indirect pathological consequences of a disease, reduction of disease progression rate, improvement of disease state, improvement, alleviation or improved prognosis do.
  • prevention' as used in the present invention means any action that suppresses the onset or delays the progression of a disease.
  • 'Protein' is used interchangeably with'polypeptide' or'peptide', for example, refers to a polymer of amino acid residues as commonly found in proteins in nature.
  • a fragment of the FGF12 protein refers to a peptide of a portion of the FGF12 protein.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • DNA is composed of four bases: adenine (A), guanine (G), cytosine (C), and thymine (T), and RNA is composed of uracil (U) instead of thymine.
  • A forms a hydrogen bond with T or U
  • C forms a hydrogen bond with the G base, and the relationship between these bases is called'complementary'.
  • mRNA messenger RNA or messenger RNA
  • RNA messenger RNA or messenger RNA
  • diabetes which is an object of treatment or prevention, is a metabolic disorder syndrome characterized by hyperglycemia caused by a lack of insulin hormone or an abnormality in insulin resistance produced by beta cells of the pancreas and further defects of both.
  • IDDM insulin-dependent diabetes
  • NIDDM insulin-independent diabetes
  • diabetes can be divided into insulin-dependent diabetes (IDDM, Type 1) and insulin-independent diabetes (NIDDM, Type 2) caused by impaired insulin resistance and insulin secretion.
  • IDDM insulin-dependent diabetes
  • NIDDM insulin-independent diabetes
  • Type 2 diabetes various complications such as heart disease, bowel disease, eye disease, neurological disease, stroke, etc. occur, which result in chronic neurological disease and cardiovascular disease due to elevated blood sugar and insulin levels for a long time.
  • the short-term hypoglycemic and hyperglycemic reactions cause acute complications.
  • Diabetes as hyperglycemia persists chronically, causes disorders in lipid and protein metabolism as well as sugar metabolism.
  • the conditions are diverse and are directly caused by hyperglycemia, and include diabetic peripheral nerve disorders, diabetic retinopathy, diabetic nephropathy, diabetic cataract, cornea, diabetic arteriosclerosis, etc. in the retina, kidney, nerve, and cardiovascular system.
  • ST8SIA1 modulates the p38MAPK/ERK signaling system in human pancreatic ⁇ cells and prevents apoptosis by inhibiting ST8SIA1 It has been identified that it has a role to play. Therefore, it can be understood that by inhibiting the expression or activity of the ST8SIA1 protein, it is possible to inhibit the occurrence or progression of diabetes by preventing the death of the pancreas, particularly ⁇ cells, due to glucose toxicity.
  • the diabetes in the present invention may be a target of diabetes caused by glucose toxicity or deep or advanced diabetes, and more specifically, selected from the group consisting of type 1 diabetes, type 2 diabetes, and gestational diabetes. Can be.
  • the term'ST8SIA1' used in the present invention refers to a gene or protein thereof encoding alpha-N-acetylneuraminide alpha-2,8-sialyltransferase. It is a type II membrane protein that moves sialic acid from CMP-sialic acid to GM3 to produce ganglioside GD3 and GT3. Ganglioside GD3 is known to be important for cell adhesion and growth of cultured malignant cells.
  • the ST8SIA1 protein (alpha-N-acetylneuraminide alpha-2,8-sialyltransferase) in the present invention may be derived from mammals, preferably derived from humans. Most preferably, the ST8SIA1 protein in the present invention comprises the amino acid sequence of human ST8SIA1 isoform 1 (NP_003025.1) represented by SEQ ID NO: 1 or human ST8SIA1 isoform 2 (NP_001291379.1) represented by SEQ ID NO: 2 Characterized in that (NCBI Genbank accession number in parentheses).
  • the ST8SIA1 protein expression inhibitor may be an antisense oligonucleotide, siRNA, shRNA, miRNA, ribozyme, crispr-cas9, DNAzyme, or protein nucleic acid (PNA) that complementarily binds to ST8SIA1 mRNA.
  • the ST8SIA1 mRNA most preferably contains a nucleotide sequence of human ST8SIA1 mRNA transcript variant 1 (NM_003034.3) represented by SEQ ID NO: 3 or human ST8SIA1 mRNA transcript variant 2 (NM_001304450.1) represented by SEQ ID NO: 4 (NCBI Genbank accession number in parentheses).
  • NM_003034.3 represented by SEQ ID NO: 3
  • human ST8SIA1 mRNA transcript variant 2 NM_001304450.1
  • SEQ ID NO: 4 NCBI Genbank accession number in parentheses
  • The'siRNA small interfering RNA or short interfering RNA or silencing RNA
  • Interference is a short double-stranded RNA that is composed of 20 to 25 nucleotides complementary to a specific site of the target mRNA.
  • an antisense strand complementary to the target mRNA binds to the RNA-induced silencing complex (RISC) protein complex and binds to the target mRNA, and the argonaute protein in the RISC complex cleaves and degrades the target mRNA. It suppresses the expression of specific genes through mechanisms such as suppressing the binding of proteins and ribosomes important for protein translation with mRNA.
  • RISC RNA-induced silencing complex
  • the shRNA according to the present invention is a substance that induces RNA interference, and is a molecule having a double-stranded structure in the molecule and a hairpin-like structure by partially containing a palindromic nucleotide sequence in a single-stranded RNA.
  • a shRNA expression plasmid is introduced into a cell and expressed, a 21-23 base pair siRNA is generated by RNase III (ribonuclease III) enzyme called dicer in the cell to induce RNAi.
  • the siRNA or shRNA according to the present invention may be obtained by applying various modifications to improve the stability of oligonucleotides in vivo, impart resistance to nucleases, and reduce non-specific immune responses.
  • the modification of the oligonucleotide is the OH group at the 2′ carbon position of the sugar structure in one or more nucleotides -CH 3 (methyl), -OCH 3 (methoxy), -NH 2 , -F, -O-2-methoxyethyl, -O-propyl, -O-2-methylthioethyl, -O-3-aminopropyl, -O-3-dimethylaminopropyl, -ON-methylacetamido or -O-dimethylami Modification by substitution with dooxyethyl; Modification in which oxygen in the sugar structure in the nucleotide is substituted with sulfur; Alternatively, one or more modifications selected from modifications of nucleotide bonds to phosphorothi
  • the ST8SIA1 protein activity inhibitor may be a compound, peptide, peptide mimetics, aptamer, antibody, natural extract or synthetic compound that specifically binds to the ST8SIA1 protein.
  • the pharmaceutical composition according to the present invention may be variously formulated according to the route of administration by a method known in the art together with a pharmaceutically acceptable carrier for the treatment of diabetes.
  • the carrier includes all kinds of solvents, dispersion media, oil-in-water or water-in-oil emulsions, aqueous compositions, liposomes, microbeads and microsomes.
  • it is formulated using a transfection reagent, and can be delivered to cells using subcutaneous, blood, bone marrow, or abdominal cavity.
  • the pharmaceutical composition according to the present invention may be administered to a patient in a pharmaceutically effective amount, that is, in an amount sufficient to prevent diabetes or alleviate and treat symptoms.
  • a typical daily dosage may be administered in the range of about 0.01 to 1000 mg/kg, and preferably, it may be administered in the range of about 1 to 100 mg/kg.
  • the pharmaceutical composition of the present invention can be administered in one or several divided doses within a preferred dosage range.
  • the dosage of the pharmaceutical composition according to the present invention may be appropriately selected by a person skilled in the art according to the route of administration, the subject of administration, age, sex, weight, individual difference and disease state.
  • the route of administration may be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, rectal, or pancreatic It may be intravenous administration, but is not limited thereto, and most preferably it is administered directly to the pancreas.
  • powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, suspensions, wafers according to a method known in the art together with a suitable carrier for oral administration. It can be formulated in the form of such as.
  • suitable carriers include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, cellulose, Fillers such as celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, gelatin, and polyvinylpyrrolidone may be included. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant. Furthermore, the pharmaceutical composition may further include an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and a preservative.
  • the pharmaceutical composition of the present invention when administered parenterally, can be formulated according to a method known in the art in the form of injections, transdermal administrations and nasal inhalants together with a suitable parenteral carrier.
  • the pharmaceutical composition can be administered by any device capable of moving the active substance to the target cell.
  • Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections or instillations.
  • injectables include aqueous solvents such as physiological saline or Ringel's solution, vegetable oils, higher fatty acid esters (e.g., ethyl oleic acid, etc.), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerin).
  • aqueous solvent etc.
  • stabilizers for preventing deterioration e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.
  • emulsifiers e.g., buffers for pH adjustment
  • Pharmaceutical carriers such as preservatives for inhibiting the growth of microorganisms (eg, phenyl mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may be included.
  • suitable carriers for injections include, but are not limited to, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), a mixture thereof and/or a solvent or dispersion medium containing vegetable oil.
  • suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose. Etc. can be used.
  • the injection may further include an isotonic agent such as sugar or sodium chloride in most cases.
  • transdermal administration ointments, creams, lotions, gels, external solutions, pasta, liniment, air rolls, and the like are included.
  • transdermal administration means that the active ingredient in an effective amount contained in the pharmaceutical composition is delivered into the skin by topically administering the pharmaceutical composition to the skin.
  • the pharmaceutical composition of the present invention may be prepared in an injectable formulation and administered by lightly pricking the skin with a 30 gauge thin injection needle or applying it directly to the skin. These formulations are described in prescriptions generally known in pharmaceutical chemistry.
  • the compounds used according to the invention can be used in pressurized packs or with suitable propellants, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered from a nebulizer in the form of an aerosol spray.
  • the dosage unit can be determined by providing a valve that delivers a metered amount.
  • gelatin capsules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.
  • compositions according to the present invention include one or more buffers (e.g., saline or PBS), carbohythrate (e.g., glucose, mannose, sucrose or dextran), antioxidants, bacteriostatic agents, chelating agents (e.g. For example, EDTA or glutathione), adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents and/or preservatives may further be included.
  • buffers e.g., saline or PBS
  • carbohythrate e.g., glucose, mannose, sucrose or dextran
  • antioxidants e.g., bacteriostatic agents, chelating agents (e.g. For example, EDTA or glutathione), adjuvants (eg, aluminum hydroxide), suspending agents, thickening agents and/or preservatives may further be included.
  • bacteriostatic agents e.g., EDTA or glutathione
  • adjuvants
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • composition of the present invention may be administered alone or may be administered in combination with a known compound that protects pancreatic cells and has an effect of treating diabetes.
  • (c) It provides a diabetes treatment screening method comprising the step of selecting a test substance that reduces the ST8SIA1 gene expression level compared to the control cells as a diabetes treatment candidate substance.
  • the step (a) is a step of contacting a cell expressing the ST8SIA1 gene in order to confirm whether the test substance to be analyzed has an activity to inhibit the expression of the ST8SIA1 gene.
  • 'contacting' is in a general sense, and combining two or more agents (eg, two polypeptides), or combining an agent and cells (eg, proteins and cells).
  • agents eg, two polypeptides
  • cells eg, proteins and cells.
  • Contact can occur in vitro. For example, combining two or more agents in a test tube or other container, or combining a test agent with cells or cell lysates and a test agent. Contact can also occur in cells or in situ.
  • two polypeptides are brought into contact in a cell or cell lysate by coexpressing a recombinant polynucleotide encoding two polypeptides in a cell.
  • a protein chip or a protein array in which the protein to be tested is arranged on the surface of a stationary bed may be used.
  • the'test substance' can be used interchangeably with a test agent or agent, and any substance, molecule, element, compound ( Includes a compound, entity, or combination thereof. Examples include proteins, polypeptides, small organic molecules, polysaccharides, and polynucleotides. It may also be a natural product, a synthetic compound or a chemical compound, or a combination of two or more substances.
  • Test formulations can be synthetic or natural. The test formulations can be obtained from a wide variety of sources, including libraries of synthetic or natural compounds. Combinatorial libraries can be produced with several types of compounds that can be synthesized in a step-by-step manner.
  • Compounds of multiple combinatorial libraries can be prepared by the encoded synthetic libraries (ESL) method (WO 95/12608, WO93/06121, WO 94/08051, WO 95/395503 and WO 95/30642).
  • Peptide libraries can be prepared by the phage display method (WO91/18980).
  • Libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts can be obtained from commercial sources or collected in the field.
  • Known pharmacological agents can be directed or applied to a random chemical modification, such as acylation, alkylation, esterification, amidification, to prepare structural analogues.
  • the test agent may be a naturally occurring protein or fragment thereof. Such test formulations can be obtained from natural sources, such as cell or tissue lysates. Libraries of polypeptide preparations can be produced, for example, by conventional methods or obtained from commercially available cDNA libraries.
  • the test agent may be a peptide, such as a peptide having about 5 to 30 amino acids, preferably about 5 to 20, more preferably about 7 to 15 amino acids.
  • the peptide may be a naturally occurring protein, a random peptide, or a cut product of a'biased' random peptide.
  • the test agent may be a nucleic acid.
  • the nucleic acid test agent can be a naturally occurring nucleic acid, a random nucleic acid, or a'biased' random nucleic acid.
  • cuts of prokaryotic or eukaryotic genomes can be used analogously to those described above.
  • test agent may be a small molecule (eg, a molecule having a molecular weight of about 1,000 Da or less).
  • a high throughput assay may be preferably applied to a method for screening a small molecule modulating agent. Many assays are useful for this screening.
  • expression means that a protein or nucleic acid is produced in a cell.
  • the cell expressing ST8SIA1 may be a cell that internally expresses ST8SIA1, or may be a cell transformed with a recombinant expression vector containing a polynucleotide encoding ST8SIA1 to overexpress ST8SIA1.
  • the cells expressing the ST8SIA1 gene may be pancreatic beta cells or cells derived from pancreatic beta cells.
  • the present inventors have used the IPCs cell line derived from human pancreatic beta cells as cells that internally express ST8SIA1.
  • the step (b) is a step of measuring the gene expression level of ST8SIA1 in cells expressing ST8SIA1 contacted with the test substance and cells expressing ST8SIA1 without contact with the test substance.
  • the method of measuring the expression level of the ST8SIA1 gene may be performed by measuring the mRNA or protein level of ST8SIA1.
  • RT-PCR reverse transcription polymerase chain reaction
  • competitive RT-PCR competitive RT-PCR
  • RPA RNase protection assay
  • northern blotting DNA microarray chip
  • RNA sequencing RNA sequencing
  • methods for measuring the expression level of proteins can be used without limitation, methods known in the art, such as western blotting, dot blotting, enzyme-linked immunosorbent assay. , Radioactive Immunoassay (RIA), Radioimmune Diffusion Method, Ouchteroni Immunity Diffusion Method, rocket immunoelectrophoresis, immunohistochemical staining, immunoprecipitation, complement fixation assay, flow cytometry (FACS) or protein chip method, etc.
  • RIA Radioactive Immunoassay
  • FACS flow cytometry
  • FACS flow cytometry
  • the step (c) is a step of selecting a test substance that reduces the expression level of the ST8SIA1 gene compared to the control cells as a candidate substance for treating diabetes.
  • the test substance that reduces the expression level of the ST8SIA1 gene reduces the protein level and the activity level of the protein of ST8SIA1 to prevent apoptosis caused by glucose toxicity in pancreatic ⁇ cells, and thus delay or symptomatic diabetes caused by this. It can be seen that it can alleviate.
  • compositions for preventing or treating diabetes comprising as an active ingredient insulin secreting cells in which the ST8SIA1 gene is deleted.
  • IPCs insulin producing cells
  • the method of producing the'ST8SIA1 gene-deleted insulin secreting cell' of the present invention is not limited thereto, but may include the following steps:
  • step (b) transfecting the exosomes isolated in step (a) with an antibody that specifically binds to ST8SIA1;
  • step (c) transfecting the exosomes prepared in step (c) into insulin secreting cells.
  • the exosome can serve as a carrier for transporting the protein of interest to the target cells or tissues of the target protein, including the protein of interest (antibody in the present invention) inside.
  • the protein of interest can be used to delete a specific gene (suppress the expression or activity of a gene) by acting on a target cell or tissue.
  • the exosomes are isolated from insulin-secreting cells, the ST8SIA1 antibody is transfected into the exosomes, and then the prepared ST8SIA1 antibody-transfected exosomes are transfected into the insulin-secreting cells. Expression or activity of the protein was knocked out. Deleting the ST8SIA1 gene of insulin-secreting cells using exosomes was the first discovery by the present inventors.
  • the insulin-secreting cells from which the ST8SIA1 gene is knocked-out when administered or transplanted to an individual, insulin secretion is increased, so that the blood sugar in the individual decreases and the ability to control blood glucose level is very excellent. there was.
  • The'insulin secreting cells' may be differentiated from stem cells, but are not limited thereto.
  • the method of differentiating insulin-secreting cells from stem cells is not limited as long as it is known, for example, Soria et al. [Soria B, Roche E, Berna G and Leon-Quinto T (2000) Insulin-secreting cells derived from embryonic stem. cells normalize glycemia in streptozotocin-induced diabetic mice. Diabetes 49, 157-162], Assady et al. [Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, and Tzukerman M. (2001) Insulin production by human embryonic stem cells.
  • the stem cells are undifferentiated cells having the ability to differentiate into various body tissues, which are classified into totipotent stem cells, pluripotent stem cells, and multipotent stem cells. Can be.
  • Stem cells in the present invention may be adult stem cells, embryonic stem cells, mesenchymal stem cells, tumor stem cells, or induced pluripotent stem cells, depending on their origin or type.
  • the term'mesenchymal stem cell (MSC)' as used herein has the ability to differentiate into various mesenchymal cells including bone, cartilage, fat, muscle cells, or ectodermal cells such as neurons. It is a multipotent stem cell.
  • the mesenchymal stem cells may preferably be derived from those selected from the group consisting of umbilical cord, umbilical cord blood, bone marrow, fat, muscle, nerve, skin, amniotic membrane, chorionic membrane, deciduous membrane, and placenta.
  • the mesenchymal stem cells may be derived from humans, fetuses, or mammals other than humans.
  • the mammals other than humans are more preferably canine, feline, monkey, cow, sheep, pig, horse, rat, mouse, guinea pig, and the like, and the origin is not limited.
  • the active ingredient is a concept including a cell culture medium containing the cells, a concentrate of a cell culture, and the like.
  • the present invention provides a use of an inhibitor of the expression or activity of the ST8SIA1 protein for preparing a preparation for preventing or treating diabetes.
  • the present invention provides a method for treating diabetes, comprising administering to an individual in need thereof an effective amount of a composition comprising an inhibitor of ST8SIA1 protein expression or activity as an active ingredient.
  • The'effective amount' of the present invention refers to an amount that improves, treats, prevents, detects, diagnoses, or inhibits or reduces diabetes when administered to an individual, and the'individual' refers to an animal, preferably a mammal , In particular, it may be an animal, including humans, and may be cells, tissues, organs, etc. derived from animals. The individual may be a patient in need of the effect.
  • The'treatment' of the present invention refers generically to improving the symptoms of diabetes or diabetes, which may include curing, substantially preventing, or improving the condition, as long as it originates from the disease. It includes, but is not limited to, alleviating, curing or preventing the symptoms or most of the symptoms.
  • the term'comprising' is used in the same manner as'containing' or'as a feature', and does not exclude additional component elements or method steps that are not mentioned in the composition or method. .
  • the term'consisting of' is used in the same way as'consisting of', and means excluding additional elements, steps, or ingredients that are not separately described.
  • the term'essentially consisting of' or'essentially consisting of' means, in the scope of a composition or method, a component element or step that does not substantially affect its basic properties in addition to the described component elements or steps. Means to include.
  • the present invention can prevent apoptosis by controlling the expression of related factors upon inhibition of ST8SIA1 in hyperglycemic conditions, decrease insulin resistance and increase sensitivity through increased tyrosine phosphorylation, and increase insulin secretion due to ST8SIA1 inhibition. It can be usefully used to develop a therapeutic agent for diabetes with a completely new mechanism of action that inhibits the expression or activity of the ST8SIA1 protein.
  • ST8SIA1 plays a role in promoting apoptosis in pancreatic beta cells under hyperglycemic conditions, lowering the activity of ST8SIA1 inhibits apoptosis caused by hyperglycemia and has the effect of protecting pancreatic beta cells.
  • antidiabetic candidate substances can be selected by screening for agents that inhibit activity.
  • insulin secretion is increased, so that blood sugar in the individual decreases and the ability to regulate blood glucose level is very excellent.
  • Figure 3 shows the change in the amount of insulin secretion when ST8SIA1 is inhibited in IPCs cells. PBS was used as a control.
  • FIG. 4 shows the results of measuring the blood glucose concentration of db/db mice by dividing 9-week-old mice into 8 mice per group and transplanting ST8SIA1KO-IPCs at 1 week of breeding.
  • 5 shows the results of measuring insulin sensitivity by dividing 9-week-old db/db mice into 8 mice per group and transplanting ST8SIA1KO-IPCs at 1 week of breeding.
  • Figure 6 is a 9-week-old db/db mice divided by 8 per group, and ST8SIA1KO-IPCs were transplanted at 1 week of breeding, and glucose tolerance was measured.
  • Figure 7 shows the results of measuring the blood glucose concentration of db/db mice by dividing 9-week-old mice into 8 mice per group, using anti-ST8SIA1-Ab as an adjuvant with 0.5% saponin and 100 ul of saponin at 1 week.
  • IPCs cells Insulin secreting cell line IPCs cells were differentiated from mesenchymal stem cells.
  • Glucose toxicity was induced by treatment with 33 mM glucose for 48 hours. Then, 10 ⁇ M ST8SIA1 antibody (ST pharm) was treated for 48 hours.
  • Cells were lysed using RIPA buffer (50mMTris-HCl, 150mMNaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS) containing protease inhibitor cocktail (Roche Diagnostics).
  • the protein composition of the cell lysate was quantified with a BCA protein assay kit (Roche Diagnostics), and then the cell lysate containing the same amount of protein was separated by SDS-PAGE. Then, the protein was transferred to Immobilon NC membranes. Blocking was performed for 1 hour with TBS and Tween 20 solution (0.05% Tween 20) containing 5% skim milk or 5% bovine albumin serum (BSV).
  • BD-MSC bone marrow derived mesenchyma stem cells
  • IPCs insulin producing cells
  • mice 9-week-old db/db mice were reared by dividing 8 mice per group. At 1 week of breeding, 3x10 6 ST8SIA1KO-IPCs were transplanted into the mouse pancreas.
  • Exosomes from 10 ml of IPCs culture media using ExoQuick kt (SBI bio). Exosomes in 500ul of sterile PBS are approximately 50-300ug.
  • 10ul Exo-Fect solution, 10ul PBS solution, 50ul purified exosomes, and ST8SIA1 antibody (20ul) were put together and mixed well by repeating 3 times.
  • the mixed exosome transfection solution was incubated with a shaker at 37° C. for 1 hour and immediately placed the tube on ice. Transfect 30ul of ExoQuickTC reagent into the exosome sample suspension, mix well and mix 6 times. Again, the transfection sample is stabilized on ice or at 4° C.
  • the sample was centrifuged for 3 minutes at 13,000-14,000 rpm in a microfuge (maximum speed), the supernatant was removed, and the transfected exosome pellet was released in 300ul 1x PBS.
  • Example 1 Effect of the expression level of ST8SIA1 on apoptosis
  • IPCs ST8SIA1KO-IPCs cells transfected with exosomes were cultured for 2 days under conditions of normal glucose (NG) or high glucose (HG: 33 mM), respectively.
  • NG normal glucose
  • HG high glucose
  • ⁇ -actin was used as a protein loading control.
  • the expression of ST8SIA1 was inhibited with the ST8SIA1 antibody under high glucose conditions and the expression level of cleaved caspase 3 was measured.
  • Diabetes is known to be mainly caused by an abnormality in sub-receptor signaling, especially inhibition of IRS-1 (insulin receptor substrate-1)-associated PI3K activity, rather than a defect in the insulin receptor (IR) itself.
  • IRS-1 insulin receptor substrate-1
  • This IRS-1-associated PI3K activity is regulated by the tyrosine phosphorylation of IRS-1 or the amount of IRS-1 protein itself, and a decrease in the amount of tyrosine phosphorylation protein of IRS-1 is observed in various diabetic animal models or diabetic environments.
  • ST8SIA1KO-IPCs cells were not treated with or treated with 100 nM insulin for 10 minutes to measure tyrosine phosphorylation by Western blot.
  • the ST8SIA1KO-IPCs group showed that blood sugar was rapidly decreased to and maintained at a normal level, whereas in the control group, it was confirmed that the blood sugar was continuously increased or increased.
  • Example 4 Effect on insulin sensitivity and glucose tolerance
  • IPGTT oral glucose tolerance test
  • glucose (dosage: 2g/kg body weight) was administered intraperitoneally (IPGTT) at 10 weeks of age.
  • Glucose levels were monitored at 60 and 120 minutes after testing by the tail bleed method.
  • insulin resistance test insulin (0.5U/kg body weight) was administered by intraperitoneal injection at 14 weeks of age. Glucose levels were monitored at 10, 20, 40 and 60 minutes after testing by tail bleed method.
  • the present invention can screen an agent that inhibits the expression or activity of ST8SIA1 to screen for antidiabetic candidate substances, and when the insulin-secreting cells from which the ST8SIA1 gene is knocked-out is administered or transplanted to an individual, insulin secretion is increased. As a result, the blood sugar in the individual decreases and the ability to control blood sugar levels is very good, so it has industrial applicability.

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Abstract

La présente invention concerne une composition pour la prévention ou le traitement du diabète à l'aide de ST8SIA1, et un procédé de criblage d'agents antidiabétiques, et, plus particulièrement, l'invention concerne : une composition pour la prévention ou le traitement du diabète, contenant, en tant que principe actif, un inhibiteur d'expression ou d'activité de protéine ST8SIA1 ou une cellule de sécrétion d'insuline dans laquelle un gène ST8SIA1 est supprimé; et un procédé de criblage d'agents antidiabétiques.
PCT/KR2020/095049 2019-03-25 2020-03-25 Composition pour la prévention ou le traitement du diabète à l'aide de st8sia1, et procédé de criblage d'agents antidiabétiques Ceased WO2020197367A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003052088A2 (fr) * 2001-12-18 2003-06-26 Bayer Healthcare Ag Regulation de la sialyltransferase humaine
WO2009150550A2 (fr) * 2008-06-13 2009-12-17 Prognomix, Inc. Composant génétique de complications dans le diabète de type 2
WO2016179417A2 (fr) * 2015-05-06 2016-11-10 The University Of Utah Research Foundation Administration d'exosomes de micro-arn
WO2017035501A1 (fr) * 2015-08-27 2017-03-02 Academia Sinica Inhibiteurs de sialyltransférase et utilisations de ceux-ci
US20180305689A1 (en) * 2015-04-22 2018-10-25 Mina Therapeutics Limited Sarna compositions and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003052088A2 (fr) * 2001-12-18 2003-06-26 Bayer Healthcare Ag Regulation de la sialyltransferase humaine
WO2009150550A2 (fr) * 2008-06-13 2009-12-17 Prognomix, Inc. Composant génétique de complications dans le diabète de type 2
US20180305689A1 (en) * 2015-04-22 2018-10-25 Mina Therapeutics Limited Sarna compositions and methods of use
WO2016179417A2 (fr) * 2015-05-06 2016-11-10 The University Of Utah Research Foundation Administration d'exosomes de micro-arn
WO2017035501A1 (fr) * 2015-08-27 2017-03-02 Academia Sinica Inhibiteurs de sialyltransférase et utilisations de ceux-ci

Non-Patent Citations (1)

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Title
RICHARD K.P. BENNINGER, DAVID J. HODSON: "New understanding of beta- cell heterogeneity and in situ islet function", DIABETES, vol. 67, no. 4, 2018, pages 537 - 547, XP055743655, DOI: 10.2337/dbi17-0040 *

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