WO2008013324A1 - Utilisation d'une protéine dérivée du foie, associée au diabète, pour le diagnostic ou le traitement du diabète de type 2 ou d'un trouble vasculaire - Google Patents

Utilisation d'une protéine dérivée du foie, associée au diabète, pour le diagnostic ou le traitement du diabète de type 2 ou d'un trouble vasculaire Download PDF

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WO2008013324A1
WO2008013324A1 PCT/JP2007/065221 JP2007065221W WO2008013324A1 WO 2008013324 A1 WO2008013324 A1 WO 2008013324A1 JP 2007065221 W JP2007065221 W JP 2007065221W WO 2008013324 A1 WO2008013324 A1 WO 2008013324A1
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selenoprotein
diabetes
type
vascular
vascular disorder
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PCT/JP2007/065221
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Japanese (ja)
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Shuichi Kaneko
Toshinari Takamura
Hirofumi Misu
Nobuyuki Takakura
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National University Corporation Kanazawa University
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Priority to JP2008526853A priority Critical patent/JP5299900B2/ja
Publication of WO2008013324A1 publication Critical patent/WO2008013324A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders

Definitions

  • Diabetes-related liver-derived secretory protein used for diagnosis or treatment of type 2 diabetes or vascular disorders
  • the present invention relates to the use of selenoprotein P for the diagnosis and treatment of type 2 diabetes or vascular disorders.
  • Type 2 diabetes which continues to increase on a global scale, threatens human Q0L and life by promoting arteriosclerotic diseases such as retinal, renal, and neurological complications and ischemic heart disease.
  • arteriosclerotic diseases such as retinal, renal, and neurological complications and ischemic heart disease.
  • the development of treatment is urgent.
  • the liver not only plays a major role in glucose and lipid metabolism, but is also the largest in-vivo producing organ of various physiologically active substances such as angiogenic factors. There is a possibility that many are produced.
  • insulin resistance see Non-Patent Documents 1 and 2). Insulin resistance leads to hyperglycemia due to increased glucose release from the liver and hyperlipidemia due to increased lipid production, both of which promote arteriosclerotic diseases.
  • the liver is the largest organ that produces various biologically active substances, including angiogenic factors that lead to the risk of arteriosclerosis.
  • Non-Patent Document 1 Michael MD. Et al., Mol. Cel l 6: 87-97, 2000
  • Non-Patent Document 2 Salt iel AR. Et al., Ature 414: 799-806, 2001
  • the present invention relates to selenoprotein P which is a secretory protein derived from diabetes-related liver.
  • a method for assessing the risk of suffering from a disorder, and selenoprote The purpose is to provide markers for detecting vascular disorders such as diabetes and arteriosclerotic diseases, and markers for assessing the risk of vascular disorders such as type 2 diabetes and arteriosclerotic diseases. .
  • the present invention relates to a method for screening a medicament for preventing or treating vascular disorders such as type 2 diabetes and arteriosclerotic diseases using selenoprotein P, and the prevention or treatment of vascular disorders containing selenoprotein P as an active ingredient.
  • the purpose is to provide medicine.
  • liver biopsy samples from more than 100 diabetic / metabolic syndrome patients, and comprehensively analyzed liver expression genes exceeding 600,000 genes using DNA chips and the SAGE method. I have done it. From these liver-expressed gene information, 62 secreted protein groups that correlate with liver gene expression and clinical indicators of patients such as glycemic control, BMI, insulin resistance, etc. were identified (Gyoen & Tsuji Kaneko et al. Genes whose expression varies in relation to the Japanese patent application, Japanese Patent Application No. 2005-125689).
  • the present inventors conducted further diligent studies on a diabetes-related liver-derived secreted protein.
  • the present inventors identified selenoprotein P as a secretory protein in which liver gene expression correlates with insulin resistance and blood glucose level 2 hours after glucose load from a comprehensive gene expression profile in the liver of type 2 diabetic patients.
  • the function was analyzed. As a result, it was found that administration of selenoprotein P to mice induces systemic insulin resistance and induces hyperglycemia after glucose loading. As a mechanism, the insulin signal in hepatocytes is attenuated and the liver is decreased. It was shown to increase sugar release from cells.
  • studies using mouse fetal organ cultures have revealed that selenoprotein P suppresses the proliferation of vascular endothelial cells and strongly induces the proliferation of vascular wall cells.
  • type 2 diabetes can be diagnosed by using selenoprotein P expression as an index because the expression of selenoprotein P gene is associated with the pathology of type 2 diabetes.
  • selenoprotein P greatly affects the action of insulin. Therefore, we found that controlling the expression of selenoprotein P can control the pathology of type 2 diabetes.
  • selenoprotein P affects the generation and proliferation of vascular cells, it has been found that it can be used for the treatment of vascular disorders, and the present invention has been completed.
  • the present invention is as follows.
  • [I] A method for detecting type 2 diabetes or vascular disorder, comprising measuring selenoprotein P.
  • a method for assessing the risk of suffering from type 2 diabetes or vascular disorders comprising measuring selenoprotein P.
  • a method for evaluating a subject's insulin resistance or glycemic control comprising measuring selenoprotein P.
  • a method for evaluating insulin resistance in patients with type 2 diabetes comprising measuring selenoprotein P.
  • a method for assessing the risk of developing type 2 glycouremia in a person with normal glucose tolerance comprising measuring selenoprotein P.
  • a marker for detecting type 2 diabetes or vascular disorder comprising selenoprotein P.
  • a marker for assessing the risk of morbidity of type 2 diabetes or vascular disorders consisting of selenoprotein P.
  • [1 4] Use of selenoprotein P as a marker for evaluation of insulin resistance or glycemic control.
  • a method for screening for preventive or therapeutic agents for type 2 diabetes or vascular disorders, which is selected as a prophylactic or therapeutic agent based on the ability to suppress the expression or action of the candidate compound selenoprotein P A screening method comprising:
  • a preventive or therapeutic agent for a disease associated with proliferation of vascular endothelial cells or decreased proliferation of vascular wall cells comprising selenoprotein P or a nucleic acid encoding selenoprotein P as an active ingredient.
  • a preventive or therapeutic agent for type 2 diabetes or vascular disorder comprising anti-selenoprotein P antibody as an active ingredient.
  • a prophylactic or therapeutic agent for type 2 diabetes or vascular disorder comprising, as an active ingredient, a double-stranded RNA that suppresses the expression of a gene encoding selenoprotein P.
  • Sense RNA consisting of a sequence homologous to a base sequence consisting of 15 to 50 bases of the base sequence encoding selenoprotein P shown in SEQ ID NO: 1 and complementary to the sense RNA Double strand consisting of antisense RNA consisting of sequence
  • Figure 1 shows the relationship between selenoprotein P and insulin resistance and arteriosclerosis.
  • FIG. 2 shows a vicious circle associated with hyperglycemia and hyperselenoproteinemia.
  • Fig. 3 shows the correlation between selenoprotein P gene expression in human liver and MCR.
  • Figure 4 shows selenoprotein P gene expression in human liver and blood glucose level for 2 hours after glucose loading. It is a figure which shows correlation of these.
  • FIG. 5 shows the effect of insulin administration on selenoprotein P gene expression in hepatocytes.
  • FIG. 6 is a graph showing the effect of glucose administration on selenoprotein P gene expression in hepatocytes.
  • FIG. 7A shows the effect of selenoprotein P on glucose release from hepatocytes.
  • Figure 7B shows the effect of selenoprotein P on glucose release from hepatocytes (part 2).
  • FIG. 8 shows the effect of selenoprotein P on the phosphorylation of Akt by insulin administration in hepatocytes.
  • FIG. 8A is a photograph showing the results of SDS-PAGE
  • FIG. 8B is a graph showing the strength of effect under each condition.
  • Figure 9 is a photograph showing the effect of selenoprotein P on fetal mouse angiogenesis.
  • Figure 9A shows the negative control
  • Figure 9B shows the results when selenoprotein P was administered at 5 Z g / mL
  • Figure 9C shows the results when selenoprotein P was administered at 25 // g / mL.
  • FIG. 10 is a graph showing the results of a glucose tolerance test on mice subjected to selenoprotein P administration.
  • FIG. 11 is a diagram showing the results of an insulin tolerance test on mice subjected to selenoprotein P administration.
  • Figure 12 shows the correlation between serum selenoprotein P concentration and BMI / QUICKI in patients with type 2 diabetes.
  • Fig. 12 A shows the correlation with BMI
  • Fig. 12 B shows the correlation with QUICKI.
  • FIG. 13 is a diagram showing the results of comparison of serum selenoprotein concentrations with and without obesity in patients with type 2 diabetes.
  • FIG. 14 is a graph showing the correlation between serum selenoprotein P concentration and body weight ′ H0MA-IR in normal glucose tolerance individuals.
  • Fig. 14 A shows the correlation with body weight
  • Fig. 14 B shows the correlation with H0MA-IR.
  • Figure 15 shows the rapid administration of hepatic selenoprotein P gene expression s iRNA to KKAy mice injected with selenoprotein P s iRNA, and RNA from the liver 7 days later. It is a figure which shows the extracted result.
  • the gene expression level was measured by Realtime PCR. ⁇ p is 0.05.
  • Figure 16 is a photograph showing blood SeP protein expression in KKAy mice injected with siRNA against selenoprotein P. siRNA was rapidly administered to mice, and blood was collected 7 days later. Selenoprotein P protein expression was evaluated by Western blotting.
  • FIG. 17 shows fasting blood glucose levels in KKAy mice injected with siRNA against selenoprotein P.
  • Selenoprotein P (Selenoprotein P, SeP) is a protein containing 10 residues of selenocystine. Selenoprotein P acts as an enzyme with dartathoperoxidase-like activity that reduces hydrogen peroxide and lipid peroxides to detoxify and controls intracellular redox.
  • SEQ ID NO: 1 shows the nucleotide sequence of DNA encoding selenoprotein P
  • SEQ ID NO: 2 shows the amino acid sequence of selenoprotein P.
  • the selenoprotein P used in the present invention can be chemically synthesized based on the above sequence information, or can be obtained as a recombinant protein using a gene recombination technique.
  • Selenoprotein is also contained in human serum and can be isolated and purified from human serum according to the method described in Saito et al., J Biol Chem 274: 2866-2871, 1999. it can.
  • Selenoprotein P used in the present invention has the amino acid sequence shown in SEQ ID NO: 2. And a protein having an amino acid sequence in which one or several amino acids have been deleted, substituted or added, and having the above-mentioned daltathione peroxidase-like activity.
  • 1 or several is 1 to 9, preferably 1 to 5, and more preferably 1 or 2. Also excluded are those lacking any of the 10-residue selenocystines.
  • a fragment of selenophine tin P can also be used.
  • the fragment of selenoprotein p is not limited, and any fragment of selenoprotein P can be used as the best.
  • Preferred is a fragment peptide consisting of a partial partial sequence of the amino acid sequence of selenoprotein P, comprising a partial sequence consisting of 10 or more amino acids, preferably 15 or more, and more preferably 20 or more.
  • a fragment in the case of using selenoprotein P as a medicine is a fragment peptide having the above-described daltathione peroxidase-like activity. Examples of such selenoprotein P fragments include the C-terminal fragment of selenoprotein P.
  • the fragment which consists of is mentioned.
  • a fragment peptide consisting of an amino acid sequence in which one or several amino acids are deleted, substituted or added, and having the above-described dartathione peroxidase-like activity is also included.
  • Blood selenoprotein P levels reflect systemic insulin resistance and the risk of developing vascular disorders.
  • Selenoprotein P can be used as a marker for detecting diseases such as type 2 diabetes and vascular disorders.
  • Vascular disorders include arteriosclerotic diseases such as myocardial infarction, cerebral infarction, and obstructive arteriosclerosis.
  • arteriosclerotic diseases such as myocardial infarction, cerebral infarction, and obstructive arteriosclerosis.
  • insulin resistance or glycemic control can be assessed.
  • it can be a predictive marker for new insulin resistance in patients with type 2 diabetes, and a predictive marker for the onset of type 2 diabetes in patients with normal glucose tolerance.
  • selenoprotein P when selenoprotein P is high, it can be evaluated that the sensitivity to insulin is attenuated. For those with normal glucose tolerance When selenoprotein P is high, it can be judged that the risk of developing type 2 diabetes is high.
  • Selenoprotein P levels are also associated with obesity and can be a criterion for complications of obesity. That is, when selenoprotein P is high, it can be determined that the patient suffers from obesity or obesity complications. Furthermore, if selenoprotein P is high, it can be evaluated and determined that insulin resistance is increased due to obesity.
  • selenoprotein p When using selenoprotein p as a marker, selenoprotein p may be detected in a sample such as blood of a subject.
  • a sample such as blood of a subject.
  • whole blood, serum or plasma can be used as the specimen sample.
  • selenoprotein P may be detected directly, or the expression of selenoprotein P may be detected by detecting selenoprotein P mRNA.
  • an immunoassay method using an anti-selenoprotein P antibody that specifically recognizes and binds to selenoprotein P can be used.
  • Anti-selenoprotein P antibody can be prepared by a known method. Examples of the immunoassay include a method using a carrier on which an anti-selenobrotin P antibody is immobilized, Western blotting, and the like.
  • Examples of the method using a solid-phased carrier include ELISA using a solid-phased microtiter plate and agglutination method using solid-phased particles, but are not limited thereto, and known immunological measurement methods Can be used to detect serum selenoprotein P.
  • Selenoprotein P mRNA can be detected by Northern blotting, RT-PCR, DNA chip (DNA microarray) and other methods. These methods can also be performed by known methods.
  • selenoprotein P is upregulated in the liver of subjects suffering from diseases such as type 2 diabetes, it may be possible to detect the expression of selenoprotein P in the liver.
  • Detect or diagnose whether a subject suffers from type 2 diabetes or vascular disorder by measuring selenoprotein P in a sample collected from the subject or measuring the expression of selenoprotein P And the risk of the subject suffering from type 2 diabetes and vascular disorders can be assessed.
  • subject is subject to sugar and lipid metabolism It is also possible to determine whether or not you are suffering from abnormal or diabetic complications and to assess the risk of suffering from it.
  • the subject can be diagnosed as having type 2 diabetes or vascular disorder, or can be assessed as having a high risk of suffering from type 2 diabetes or vascular disorder in the subject.
  • the pathological condition of type 2 diabetes in the subject can be determined.
  • the subject's insulin resistance and blood glucose control can be evaluated.
  • the evaluation of insulin resistance refers to the determination of whether or not a subject has insulin resistance and the evaluation of the risk of becoming insulin resistance.
  • the evaluation of the blood glucose control means an evaluation of the quality of the subject's blood glucose control or an evaluation of the risk of deterioration of the blood glucose control of the subject.
  • selenoprotein P when selenoprotein P is measured in a sample collected from a subject and the selenoprotein P concentration is higher than the selenoprotein P concentration in a normal human sample sample, or the expression of selenoprotein P in the subject If is elevated, it can be assessed that the subject is resistant to insulin or that glycemic control has deteriorated. Alternatively, it can be evaluated that the subject has a high risk of becoming insulin resistant or has a high risk of worsening glycemic control. Serum protein P concentration or the expression level of selenoprotein P in specimens of normal subjects should be measured in advance, and abnormal values of serum selenoprotein p and abnormal expression cutoff values may be set by statistical analysis. Is possible.
  • the present invention also includes a test method for evaluating the risk and a test reagent for evaluating the risk.
  • Selenoprotein P can also be used as a screening marker for evaluating the above risks.
  • the present invention further includes a method for screening a drug for preventing or treating type 2 diabetes or vascular disorder using selenoprotein P expression as an index.
  • Selenoprotein P can be a therapeutic target for type 2 diabetes and arteriosclerotic lesions.
  • In diabetics there may be a vicious circle of hyperglycemia, increased secretion of selenoprotein P from the liver, worsening systemic insulin resistance, and further hyperglycemia
  • the medicament is a medicament that suppresses the expression of selenoprotein p in the body, suppresses the secretion of selenoprotein P, or inhibits the action of selenoprotein P.
  • the medicament can attenuate insulin resistance and improve glycemic control.
  • These drugs are selenobrotin secretion inhibitors or selenoprotein attenuating drugs, and can reduce blood selenoprotein P concentration to an appropriate level.
  • the medicament is, for example, a compound that can bind to the promoter of selenoprotein P and suppress the expression and secretion of selenoprotein P.
  • the medicament is a compound that binds to a selenoprotein P receptor, inhibits selenoprotein P from binding to the receptor, and can inhibit the action of selenoprotein P.
  • Such compounds include, for example, DNAs encoding selenoprotein P and selenoprotein P promoters introduced into animal cells, etc., constructing a selenoprotein P expression system, and contacting the animal cells with the candidate compound, that is, candidate compounds Animal cells can be cultured in the presence of, and screened using the expression of selenoprotein P in the cells as an indicator. When the expression of selenoprotein P is reduced by a candidate compound, the candidate compound can be selected as a pharmaceutical agent for the prevention and treatment of type 2 diabetes and vascular disorders.
  • selenoprotein P, selenoprotein P receptor, and candidate compounds coexist, and the binding of selenoprotein P to the selenoprotein P receptor is inhibited by the trapping compound, and the action of selenoprotein P is suppressed.
  • the compound can be used as a pharmaceutical for the prevention and treatment of type 2 diabetes and vascular disorders can be selected.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, selenoprotein P or a fragment peptide of selenoprotein P, which has a peptide having dartathione peroxidase-like activity, and a nucleic acid encoding selenoprotein P. Or a fragment nucleotide thereof having dartathione peroxidase-like activity
  • a pharmaceutical composition containing a fragment nucleotide that codes for a peptide as an active ingredient is included.
  • Selenoprotein P can suppress the proliferation of vascular endothelial cells and induce the proliferation of vascular wall cells, so it can be used for the prevention or treatment of diseases related to the proliferation of vascular endothelial cells or the decreased proliferation of vascular wall cells .
  • the pharmaceutical composition acts directly on vascular cells and can be used as a preventive or therapeutic agent for the above-mentioned diseases.
  • the present invention further includes a pharmaceutical composition comprising an elenoprotein P agonist or an antagonist of selenoprotein P as an active ingredient.
  • the selenoprotein P antagonist refers to a substance that binds to the selenoprotein P receptor and exerts a physiological activity in the cell.
  • the selenoprotein P antagonist refers to the selenoprotein P receptor.
  • Selenoprotein p agonists or antagonists can be used to prevent or treat diseases associated with vascular endothelial cell proliferation or vascular wall cell proliferation reduction.
  • diseases related to the proliferation of vascular endothelial cells or the decrease in the proliferation of vascular wall cells include arteriosclerotic diseases such as diabetic retinopathy, myocardial infarction, cerebral infarction, and obstructive arteriosclerosis.
  • arteriosclerotic diseases such as diabetic retinopathy, myocardial infarction, cerebral infarction, and obstructive arteriosclerosis.
  • selenoprotein p can suppress angiogenesis
  • selenoprotein P or selenoprotein p agonist or antagonist can also be used for the prevention or treatment of cancer.
  • the protein or fragment peptide When selenoprotein P protein or fragment peptide is used as a medicine, the protein or fragment peptide may be administered to the subject.
  • the nucleic acid or nucleotide when a nucleic acid encoding selenoprotein p or a fragment nucleotide thereof is used as a medicine, the nucleic acid or nucleotide may be administered into the body by a known gene therapy technique.
  • Methods for introducing a gene into a subject include a method using a viral vector and a method using a non-viral vector, and various methods are known (separate experimental medicine, basic technology of gene therapy, Yodosha, 1996; Separate Experimental Medicine, Gene Transfer & Expression Analysis Experimental Method, Yodosha, 1997; edited by Japanese Society of Gene Therapy, Gene Therapy Development Research Handbook, NTS, 1999).
  • the present invention also includes a pharmaceutical that targets selenoprotein P and can suppress the activity of selenoprotein P or the expression of selenoprotein P.
  • These medicaments can be used as preventive or therapeutic agents for type 2 diabetes or vascular disorders.
  • Examples of such a compound that can be used as a medicament include an anti-selenoprotein P antibody capable of neutralizing the action of selenoprotein P.
  • An anti-selenoprotein P antibody capable of neutralizing the action of selenoprotein P that is, an antagonistic antibody against selenoprotein P can be prepared by a known antibody production method.
  • These antibodies are preferably genetically modified antibodies that have been artificially modified for the purpose of reducing the heterologous antigenicity to humans, such as chimeric antibodies and humanized antibodies. These modified antibodies can be produced using known methods.
  • a chimeric antibody consists of a variable region of a mammal-derived antibody other than human and a constant region derived from a human antibody.
  • a humanized antibody consists of a complementarity determining region of a mammal-derived antibody other than human, a framework region derived from a human antibody, and a C region.
  • a humanized antibody is useful as an active ingredient of the therapeutic agent of the present invention because its antigenicity in the human body is reduced.
  • a humanized antibody is also called a reshaped human antibody, and the complementarity determining region (CDR) of a mammal other than human, for example, a mouse antibody, is transplanted to the complementarity determining region of the human antibody. It can be obtained by doing. It also includes a human antibody that can be obtained by introducing a human antibody locus and administering an antigen to a transgenic animal having the ability to produce a human-derived antibody.
  • the anti-selenoprotein P antibody of the present invention is a part (partial fragment) of the anti-selenoprotein P antibody, and includes a fragment of an antibody having an action on the antigen of the antibody. Specifically, F (ab ′) 2 , Fab ′, Fab, Fv, disulfide bond Fv, single chain Fv (scFv), and polymers thereof.
  • Target selenoprotein P and can suppress the activity of selenoprotein P or can be used as drugs that can suppress the expression of selenoprotein P bind to the receptor for selenoprotein p. Also included are dominant negative mutants that do not have the action of wild-type selenoprotein P and inhibit the binding of wild-type selenoprotein P to the receptor. Furthermore, compounds that can be used as pharmaceuticals that target selenoprotein P, suppress selenoprotein P activity, or suppress selenoprotein P expression include compounds that can suppress selenoprotein P expression in the body. .
  • RNAi RNA interference
  • siRNA short interfering RNA
  • siRNA is formed from double-stranded RNA (dsRNA) by being processed by Dicer in cells or in vivo.
  • dsRNA double-stranded RNA
  • Examples of the compound include double-stranded RNA having RNAi action.
  • Double-stranded RNA consists of a sense RNA consisting of a sequence homologous to the mRNA sequence of the target gene and an antisense RNA consisting of a complementary sequence thereto.
  • the sense strand or the antisense strand may have an overhang at the 3, terminal, and the type and number of bases of the overhang are not limited, for example, 1 to 5, preferably 1 to 3, More preferred is a sequence consisting of 1 or 2 bases, such as UU and TT.
  • the term “overhang” refers to a base added to the end of one strand of the shRNA and having no base capable of complementary binding to the corresponding position of the other strand.
  • the overhang may be a base constituting DNA.
  • the double-stranded part consists of an RNA strand (sense strand) having a sequence that can hybridize to the target sequence in the sequence of the target gene whose expression is to be suppressed by RNA interference, and an RNA strand (antisense strand) complementary to the sequence.
  • RNA strand sense strand
  • antisense strand complementary to the sequence.
  • the double-stranded RNA may be a short hairpin RNA (shRNA) having a stem-loop structure in which a sense strand and an antisense strand are linked via a loop sequence.
  • the specific target sequence of the gene encoding selenoprotein P which is the target gene of the double-stranded RNA of the present invention, is a sequence in RNA corresponding to the base sequence of DNA shown in SEQ ID NO: 1, and based on the sequence information Can be set appropriately.
  • the number of bases is not limited and is selected in the range of 15 to 500 bases. Preferably 15 to 50, 15 to 45, 15 to 40, 15 to 35 or 15 to 30 bases, more preferably 20 to 35 bases, more preferably 19 to 30 bases, particularly preferably 19 to 29 bases Or 28 bases.
  • an antisense nucleic acid is mentioned as a compound which can suppress the expression of selenoprotein P in the body.
  • An antisense nucleic acid is DNA or RNA that is complementary to and hybridizes to a target gene of interest, and can suppress the expression of the target gene.
  • the antisense nucleic acid that suppresses the expression of selenoprotein P of the present invention is a nucleic acid complementary to the nucleotide sequence of DNA encoding selenoprotein P shown in SEQ ID NO: 1 or a part of the RNA sequence corresponding to the DNA sequence. It is.
  • the nucleic acid has a length of 10 to 400 nucleotides, preferably has a length of 250 or less, more preferably has a length of 100 or less, more preferably has a length force of S 50 or less, particularly preferably It is between 12 and 28 nucleotides in length.
  • Examples of the method for introducing the double-stranded RNA or antisense nucleic acid of the present invention include a hydrodynamic method, a method using canoleum ion, an electroporation method, a squib mouth plast method, a lithium acetate method, a calcium phosphate method, Examples include the ribofusion method and the microinjection method.
  • the present invention includes a pharmaceutical composition for treating or preventing type 2 diabetes or vascular disorder comprising the above compound as an active ingredient.
  • the pharmaceutical composition of the present invention comprises a selenoprotein P protein or a fragment peptide thereof, a nucleic acid encoding selenoprotein P, or a vector containing the fragment nucleotide, and a pharmacologically acceptable carrier, diluent or excipient.
  • a pharmacologically acceptable carrier diluent or excipient.
  • composition of the present invention can be administered in various forms, orally by tablets, capsules, granules, powders, syrups, etc., or injections, drops, suppositories, sprays, eye drops, Examples include parenteral administration by nasal administration and patch.
  • the pharmaceutical composition of the present invention can be administered locally.
  • the effect can be exerted by administering the composition to the liver tissue site by injection.
  • the pharmaceutical composition of the present invention contains a carrier, a diluent, and an excipient that are commonly used in the pharmaceutical field.
  • lactose and magnesium stearate are used as carriers and excipients for tablets.
  • Aqueous solutions for injection include saline, glucose and Isotonic solutions containing other adjuvants are used, and may be used in combination with appropriate solubilizers such as polyalcohols such as alcohol and propylene glycol, nonionic surfactants and the like. Sesame oil, soybean oil and the like are used as the oily liquid, and benzyl benzoate, benzyl alcohol and the like may be used in combination as the solubilizing agent.
  • oral administration is about 0.001 mg to 100 mg per day, and may be administered once or divided into several times.
  • 0.001 mg to 100 mg may be administered by subcutaneous injection, intramuscular injection, or intravenous injection.
  • selenoprotein P-encoding nucleic acid or a fragment nucleotide thereof inserted into an expression vector or the like to be translated in a subject is injected subcutaneously at a dose of 0.001 mg to 100 mg once every several days, weeks or months. It can be administered by intramuscular injection or intravenous injection.
  • administration may be carried out so that at least one copy of double-stranded RNA or antisense nucleic acid is introduced per liver cell.
  • the present invention will be specifically described by the following examples, but the present invention is not limited to these examples.
  • Rat hematoma-derived H4I IEC cells were purchased from American Type Culture Collection (ATCC). Human-derived selenoprotein P was provided by Professor Kazuhiko Takahashi (Hokkaido Pharmaceutical University, Japan) (Sai to Y. et al., J Biol Chem 274: 2866-2871, 1999). Serenoprotein P concentration was measured using the blood-fod method with ushi serum albumin as a standard. Human recombinant insulin was purchased from Sigma Chemicals. Anti-Akt antibody and anti-serine (473) phosphorylated Akt antibody were purchased from Cel Signal Technology. The anti-CD31 monoclonal antibody was purchased from Pharmingen, and the HRP-conjugated anti-human smooth muscle actin antibody was purchased from DAKO Cytomat ion.
  • mice Female C57BL / 6J mice were purchased from Sankyo Lab Service (Japan) at the age of 8 weeks and maintained in a standard light (12 hours light / dark) and temperature environment. These mice were housed in 5 cages per group, provided water and food in ad ibi tum, and used for experiments at about 10 weeks of age.
  • Example 1 Selenoprotein P gene expression and pathology of diabetes Relationship between selenoprotein P gene expression in human liver and insulin resistance Ginsulin resistance mainly in skeletal muscles, and glucose metabol ic c Quantified as learance rate (MCR).
  • MCR reflects insulin-dependent sugar uptake into skeletal muscle, and the lower the MCR, the stronger the insulin resistance.
  • Figure 3 As shown in Fig. 3, the expression level of selenoprotein P gene in human liver quantified using a DNA chip was negatively correlated with MCR, an insulin resistance index. In other words, it was found that selenoprotein P gene expression in human liver is increased in relation to insulin resistance.
  • H4I IEC Hepatocytes (H4I IEC) on a 6-well plate Dulbecco's Mod if ied Eagle medium (DMEM)
  • Biosys tems b (Assays-on-Demand gene express ion product) 0 16s rRNA was used as a control gene for normalization. PCR conditions were 50 ° C ⁇ 2 minutes for 1 cycle, 95 ° C ⁇ 10 minutes for 1 cycle, then 95 ° C for 15 seconds and 60 ° C for 1 minute for 40 cycles. To exclude the effect of osmotic pressure, mannitol at the same concentration as glucose was used as a control.
  • Hepatocytes H4IIEC were cultured on a 6-well plate to 80% confluent in DMEM medium, 20% horse serum, 5% FBS. After washing the cells once with PBS, the cells were incubated with gluconeogenic buffer (glucose-free DMEM, 3.7 g / L sodium bicarbonate) and 0.4% FBS for 6 hours for starvation. Thereafter, glucose was added to the medium and incubated for 6 hours, and total RNA was recovered using the Quick gene system (FUJI FILM). To exclude the effect of osmotic pressure, mannitol at the same concentration as glucose was used as a control.
  • gluconeogenic buffer glucose-free DMEM, 3.7 g / L sodium bicarbonate
  • Insulin controls blood glucose by inhibiting gluconeogenesis from the liver.
  • FIGS. 7A and B The results are shown in FIGS. 7A and B.
  • insulin inhibited gluconeogenesis from hepatocytes in a dose-dependent manner.
  • insulin inhibited the hepatic gluconeogenesis inhibitory effect. This indicates that Serenob Mouth Tin P attenuates the insulin action in the liver.
  • Hepatocytes H4IIEC were cultured on a 6-well plate to 80% confluent in DMEM medium, 20% horse serum, 5% FBS. After washing the cells once with PBS, the cells were cultured with serum-free DMEM medium for 6 hours in the presence of selenoprotein P 0, 1, 5, 10 / zg / mL.
  • PVDMs polyvinylidene difluoride membranes
  • selenoprotein P inhibited serine phosphorylation of Akt in a dose-dependent manner. Since selenoprotein P concentration in normal human blood is reported to be 5.3 / ig / mL (Takahashi et al., Journal of Health Science 47, Pages 346-352, 2001), selenoprotein P is normal human blood. It was found that concentrations close to medium levels can suppress the insulin action in the liver.
  • Prolonged diabetes causes retinal, renal, neuronal microvascular disorders, and arteriosclerotic diseases such as ischemic heart disease and cerebral infarction. Therefore, we first examined the effect of selenoprotein P on the pathogenesis of these vascular complications using vascular cells in vitro. In the experiment, a mouse fetal organ culture system (Takakura et al., Cell 102: 199-20, 2000) was used.
  • the stromal cell line 0P9 (Nakano T. et al., Science 265: 1098-1101, 1994) was added to alpha— modi 1 led minimum essential media (a—MEM Gibco BR, 20% Fetal-calf serum (FCS; The fetus was removed from the 8th and 5th day of gestation, and the paraaortic mesoderm (PAS) region, which is one of the origins of vascular stem cells, was isolated from the umphalomesenteric artery.
  • a—MEM Gibco BR 20% Fetal-calf serum
  • FCS Fetal-calf serum
  • Selenoprotein P 1 ⁇ g / gBW or vehicle was administered intraperitoneally twice a day at 7 am and 7 pm to five 10-week-old female C57BL / 6J mice per group. Mice were fasted after the first injection. Two hours after the second injection, 1.5 mg / gBW of glucose was intraperitoneally administered, and blood glucose levels were measured from 0 to 120 minutes. Blood glucose levels were measured using FreeStyle (Kitssey Japan).
  • P 1 ⁇ g / gBW or vehicle was administered intraperitoneally twice at 7 am and 7 pm. Mice were fasted 2 hours before the second injection. After a total of 4 hours of fasting, 0.5 mU / gBW human insulin (Humalin R (registered trademark), Lilly Japan) was administered intraperitoneally, and blood glucose levels were measured from 0 to 120 minutes. Blood glucose levels were measured using FreeStyle (Kitssey, Japan).
  • Insulin resistance in patients with normal glucose tolerance was evaluated by calculating the homeostasis model for insulin resistance (H0MA—IR) 1 as follows (Matthews DR et al., Diabetologia 28: 412-419, 1985). .
  • Insulin resistance in patients with type 2 diabetes was evaluated by calculating quantitative insulin sensitivity check index (QUICKI) as follows (Arie Katz et al., J Clin Endocrinol Metab 85: 2402-2410).
  • H0MA- IR Fasting blood glucose level (mg / dL)
  • X Fasting blood insulin concentration (// U / ml) / 405
  • QUICKI l / [log Fasting blood insulin concentration ( ⁇ U / ml) + log Fasting blood glucose level (mg / dL)]
  • the mean concentration was 5.28 ⁇ 1.3 ⁇ g / mL.
  • the patient's selenoprotein P level was positively correlated with BMI and negatively correlated with QUICKI (Figs. 12 and 3 ⁇ 4).
  • Serum selenoprotein P concentrations in patients with type 2 diabetes were compared and examined with and without obesity.
  • serum selenoprotein P level is a clinical marker that strongly reflects obesity and insulin resistance.
  • a correlation between serum selenoprotein P levels and obesity / insulin resistance was observed in both type 2 diabetics and normal glucose tolerance.
  • selenoprotein P is considered to be one of the insulin resistance-causing hormones. Therefore, human serum selenoprotein P level measurement is a novel marker for evaluating insulin resistance in patients with type 2 diabetes. In addition, it can be a predictive marker for the onset of type 2 diabetes in patients with normal glucose tolerance.
  • selenoprotein P is one of the hormones that cause insulin resistance and hyperglycemia in type 2 diabetes. Therefore, we examined whether suppression of selenoprotein P production in the liver using short interference RNA (siRNA) could be a new treatment for type 2 diabetes.
  • siRNA short interference RNA
  • siRNA specific to selenoprotein P was introduced using the hydrodynamic method. Zender, L. et al. Proc Natl Acad Sci U S A 100, 7797-802
  • SiRNA for animal introduction was purchased from Amb ion (Silencer® In
  • mice Seppl 5 '-GGUGUCAGAACACAUCGCAtt-3'
  • Negative control siRNA (sense) (The sequence of self-excluding tt is shown in SEQ ID NO: 3).
  • Negative control siRNA was purchased from Amb ion. The negative control siRNA does not have significant homology to any known gene in mouse, rat or human. After general anesthesia of the mice with Bent Barbitool, 2 nmol of siRNA was dissolved in 3. OmL of PBS and administered via the tail vein for about 15-20 seconds. s A 12-hour post-fasting glucose tolerance test and an insulin tolerance test were performed 2-7 days after siRNA administration. 0. 3 mg / g body weight of gnolecose or 4 U / kg body wei ght of the engine was administered intrathecally and blood glucose was measured 15, 30, 60 and 120 minutes later.
  • liver-derived selenoprotein P is an important therapeutic target for type 2 diabetes. Furthermore, it has been shown that liver-derived selenoprotein P may be a therapeutic target for other insulin resistance-related diseases such as arteriosclerosis and metabolic syndrome.
  • Selenoprotein P is one of the causative hormones for insulin resistance and vascular scab damage, and measurement of selenoprotein P concentration is useful as a new clinical marker that reflects the risk of systemic insulin resistance or the development of vascular disorders. is there. Using selenoprotein P as a marker, it is possible to determine the pathology of diseases such as type 2 diabetes and arteriosclerotic diseases.
  • drugs containing these selenoprotein P or selenoprotein P inhibitory therapy can be a breakthrough treatment for vascular disorders.
  • selenoprotein P may be a therapeutic target for type 2 diabetes and atherosclerotic lesions. Particularly in diabetic patients, there is a possibility that a vicious circle of hyperglycemia, increased secretion of selenoprotein P from the liver, deterioration of insulin resistance throughout the body, and further hyperglycemia may occur. Can be dramatically improved in the pathology associated with glycotoxicity.

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Abstract

La présente invention concerne l'utilisation de la sélénoprotéine P pour le diagnostic ou le traitement du diabète de type 2 ou d'un trouble vasculaire. L'invention concerne spécifiquement un procédé permettant de détecter un diabète de type 2 ou un trouble vasculaire et consistant à mesurer la sélénoprotéine P, un procédé permettant d'évaluer le risque de souffrir d'un diabète de type 2 ou d'un trouble vasculaire, un procédé permettant d'évaluer la résistance à l'insuline ou de réguler le glucose sanguin chez un sujet, et un agent thérapeutique destiné au traitement d'un diabète de type 2 ou d'un trouble vasculaire, ledit agent étant ciblé sur la sélénoprotéine P.
PCT/JP2007/065221 2006-07-28 2007-07-27 Utilisation d'une protéine dérivée du foie, associée au diabète, pour le diagnostic ou le traitement du diabète de type 2 ou d'un trouble vasculaire WO2008013324A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US9233204B2 (en) 2014-01-31 2016-01-12 Aseko, Inc. Insulin management
WO2016039426A1 (fr) * 2014-09-10 2016-03-17 国立大学法人金沢大学 Méthode d'aide à la sélection de médicament thérapeutique pour un patient atteint du diabète de type 2, méthode de prédiction de l'effet de médicament thérapeutique, méthode d'inspection, et méthode de traitement
US9483619B2 (en) 2012-09-11 2016-11-01 Aseko, Inc. Means and method for improved glycemic control for diabetic patients
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002060346A (ja) * 2000-05-19 2002-02-26 Chemo Sero Therapeut Res Inst 新規な虚血・再灌流障害抑制剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002060346A (ja) * 2000-05-19 2002-02-26 Chemo Sero Therapeut Res Inst 新規な虚血・再灌流障害抑制剤

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BECKETT G.J.: "Selenium and endocrine systems", JOURNAL OF ENDOCRINOLOGY, vol. 184, no. 3, 2005, pages 455 - 465, XP003020622 *
DREHER I.: "Cloning and Characterization of the Human Selenoprotein P Promoter: Response of Selenoprotein P Expression to Cytokines in Liver Cells", J. BIOL. CHEM., vol. 272, no. 46, 1997, pages 29364 - 29371, XP002952745 *
HARA S.: "Effects of Selenium Deficiency on Expression of Selenoproteins in Bovine Arterial Endothelial Cells", BIOL. PHARM. BULL., vol. 24, no. 7, 2001, pages 754 - 759, XP003020615 *
KARLSON H.K.R.: "Relationship between serum amyloid A level and Tanis/SelS mRNA expression in skeletal muscle and adipose tissue from healthy and type 2 diabetic subjects", DIABETES, vol. 53, no. 6, 2004, pages 1424 - 1428, XP003020619 *
KOYAMA H.: "Seikatsu Shukanbyo Yobo kara Mita Biryo Genso Selenium", THE KITAKANTO MEDICAL JOURNAL, vol. 54, no. 3, 2004, pages 272, XP003020621 *
MCCLUNG J.P.: "Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase", PROC. NATL. ACAD. SCI. USA, vol. 101, no. 24, 2004, pages 8852 - 8857, XP003020618 *
MOSTERT V.: "Selenoprotein P: Properties, Functions, and Regulations", ARCH. BIOCHEM. BIOPHYS., vol. 376, no. 2, 2000, pages 433 - 438, XP002300100 *
NARUSE T.: "Selenoprotein-P", KAKETSUKEN SHOHO REIMEI, vol. 11, 2002, pages 1 - 18, XP003020620 *
PILLAY T.S.: "Enhancement of epidermal growth factor (EGF) and insulin-stimulated tyrosine phosphorylation of endogenous substrates by sodium selenate", FEBS LETT., vol. 308, no. 1, 1992, pages 38 - 42, XP003020623 *
TABI I.: "Biofactor Kenkyu no Breakthrough: 'Glutathione' (6) Glutathione Peroxidase", VITAMIS (JAPAN), vol. 76, no. 11, 2002, pages 545 - 549, XP003020617 *
TAKASHIMA K.: "Selenoprotein P, extracellular glutathione peroxidase wa Sanka LDL-chu no Kasanka Shishitsu o Kangen suru", SEIKAGAKU, vol. 72, no. 8, 2000, pages 1064, ABSTR. NO. 3P-506, XP003020616 *

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