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WO2016005424A1 - Méthodes d'évaluation de l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux d'un patient, et de traitement du syndrome métabolique - Google Patents

Méthodes d'évaluation de l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux d'un patient, et de traitement du syndrome métabolique Download PDF

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WO2016005424A1
WO2016005424A1 PCT/EP2015/065550 EP2015065550W WO2016005424A1 WO 2016005424 A1 WO2016005424 A1 WO 2016005424A1 EP 2015065550 W EP2015065550 W EP 2015065550W WO 2016005424 A1 WO2016005424 A1 WO 2016005424A1
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ptgds
expression
expression level
reference value
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Frédéric JAISSER
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Universite Pierre et Marie Curie
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
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Universite Pierre et Marie Curie
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Descartes
Universite Paris Diderot Paris 7
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • 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
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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
    • C12Q2600/112—Disease subtyping, staging or classification
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/723—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/99—Isomerases (5.)
    • 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
    • G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to methods for assessing mineralocorticoid receptor activation in adipose tissue of a subject.
  • Metabolic syndrome is characterized by a combination of medical disorders strongly associated with the development of cardiovascular diseases and diabetes, two of the major causes of dead according to World Health Organization. MetS associates three or more of the following five clinical variables: blood pressure, abdominal adiposity (given as waist circumference), and fasting values of high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose. Adipose tissue is central in the pathogenesis of MetS: Adipose tissue is not only the energy store of the body, but accordingly to its hormonal functions, it is able to tune food intake, insulin sensitivity and secretion, the vascular function, and the general level of inflammation and oxidative stress status of the body. A better knowledge of molecules either influencing adipose tissue functions or produced by it, is currently a major task in the field.
  • the hormone Aldosterone is produced by the cortex of the adrenal gland and participates to the control of blood pressure through the regulation of salt and water reabsorption in the renal collecting ducts via activation of its receptor, the mineralcorticoid receptor (MR).
  • MR is a ligand-activated transcription factor whose expression pattern is broader that initially anticipated.
  • evidences were accumulated that MR expression and activation leads to major pathophysiological consequences in organs like heart, vessels, eye and skin, extending the potential therapeutic use of pharmacological MR antagonists.
  • These novel non-classical targets also include adipocytes where its role is still debated.
  • aldosterone is a potential risk factor for diabetes involving mechanisms independent of its effect on blood pressure.
  • a high prevalence (10-50%) of glucose intolerance and/or diabetes has been reported in primary aldosteronism (PA), and these metabolic disturbances were corrected by surgical removal of the aldosterone-producing adenoma.
  • MRA mineralocorticoid receptor antagonism
  • the present invention relates to methods for assessing mineralocorticoid receptor activation in adipose tissue of a subject.
  • the present invention is defined by the claims.
  • the present invention relates to a method for assessing mineralocorticoid receptor activation in the adipose tissue of a subject comprising the steps of i) determining the expression level of PTGDS in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) concluding of the mineralocorticoid receptor activation in the adipose tissue of the subject when the expression level determined at step i) is higher than the predetermined reference value.
  • the term "subject” denotes a mammal, such as a rodent, a feline, a canine, and a primate.
  • a subject according to the invention is a human.
  • the subject suffers from obesity.
  • the term “obesity” refers to a condition characterized by an excess of body fat. The operational definition of obesity is based on the Body Mass Index (BMI), which is calculated as body weight per height in meter squared (kg/m 2 ).
  • BMI Body Mass Index
  • Obesity refers to a condition whereby an otherwise healthy subject has a BMI greater than or equal to 30 kg/m 2 , or a condition whereby a subject with at least one co- morbidity has a BMI greater than or equal to 27 kg/m 2 .
  • An "obese subject” is an otherwise healthy subject with a BMI greater than or equal to 30 kg/m 2 or a subject with at least one comorbidity with a BMI greater than or equal 27 kg/m 2 .
  • a "subject at risk of obesity” is an otherwise healthy subject with a BMI of 25 kg/m 2 to less than 30 kg/m 2 or a subject with at least one co-morbidity with a BMI of 25 kg/m 2 to less than 27 kg/m 2 .
  • the increased risks associated with obesity may occur at a lower BMI in people of Asian descent.
  • “obesity” refers to a condition whereby a subject with at least one obesity-induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, has a BMI greater than or equal to 25 kg/m 2 .
  • An “obese subject” in these countries refers to a subject with at least one obesity- induced or obesity-related co-morbidity that requires weight reduction or that would be improved by weight reduction, with a BMI greater than or equal to 25 kg/m 2 .
  • a "subject at risk of obesity” is a person with a BMI of greater than 23 kg/m 2 to less than 25 kg/m 2 .
  • the subject suffers from metabolic syndrome.
  • Metabolic Syndrome is present if a person has three or more of the following symptoms: abdominal obesity, hyperglyceridemia, low HDL cholesterol, high blood pressure, and high fasting plasma glucose. The criteria for these symptoms are defined in the third Report of the National Cholesterol Education Program Expert Panel in Detection, Evaluation and Treatment of High blood Cholesterol in Adults (Ford, ES. et al. 2002).
  • MR nuclear receptor subfamily 3, group C, member 2,
  • NRC2 nuclear receptor subfamily 3, group C, member 2,
  • the mineralocorticoid receptor is also called aldosterone receptor.
  • PSGDS has its general meaning in the art and refers to prostaglandine D2 synthase.
  • the sample is an adipose tissue sample or a blood sample.
  • blood sample refers to a whole blood, serum, or plasma sample.
  • Determination of the expression level of PTGDS can be performed by a variety of techniques. Typically, the determination comprises contacting the sample with selective reagents such as probes, primers or ligands, and thereby detecting the presence, or measuring the amount of nucleic acids or proteins of interest (i.e. PTGDS) originally in the sample.
  • the expression level may be determined by determining the quantity of mR A in an adipose tissue sample obtained from the subject.
  • the nucleic acid contained in the samples is first extracted according to standard methods, for example using lytic enzymes or chemical solutions or extracted by nucleic-acid-binding resins following the manufacturer's instructions.
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis) and/or amplification (e.g., RT-PCR).
  • the expression level PTGDS is determined by RT-PCR, typically quantitative or semi-quantitative RT-PCR, even more typically real-time quantitative or semi-quantitative RT-PCR.
  • Other methods of amplification include ligase chain reaction (LCR), transcription-mediated amplification (TMA), strand displacement amplification (SDA) and nucleic acid sequence based amplification (NASBA).
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more typically 85% identical and even more typically 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. A wide variety of appropriate indicators are known in the art including, fluorescent, radioactive, enzymatic or other ligands (e. g. avidin/biotin).
  • Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more typically of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they typically hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a preferred kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the expression level may be determined by determining the quantity of the PTGDS protein in a blood sample obtained from the subject.
  • the methods of the invention comprise contacting the biological sample with a binding partner capable of selectively interacting with the PTGDS protein present in the blood sample.
  • the binding partner may be an antibody that may be polyclonal or monoclonal, typically monoclonal. In another embodiment, the binding partner may be an aptamer.
  • Polyclonal antibodies of the invention or a fragment thereof can be raised according to known methods by administering the appropriate antigen or epitope to a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
  • a host animal selected, e.g., from pigs, cows, horses, rabbits, goats, sheep, and mice, among others.
  • Various adjuvants known in the art can be used to enhance antibody production.
  • antibodies useful in practicing the invention can be polyclonal, monoclonal antibodies are preferred.
  • Monoclonal antibodies of the invention or a fragment thereof can be prepared and isolated using any technique that provides for the production of antibody molecules by continuous cell lines in culture. Techniques for production and isolation include but are not limited to the hybridoma technique originally and the EBV-hybridoma technique. Alternatively, techniques described for the production of single chain antibodies (see e.g. U.S. Pat. No. 4,946,778) can be adapted to produce anti-PTGDS, single chain antibodies.
  • Antibodies useful in practicing the present invention also include anti-PTGDS fragments including but not limited to F(ab')2 fragments, which can be generated by pepsin digestion of an intact antibody molecule, and Fab fragments, which can be generated by reducing the disulfide bridges of the F(ab')2 fragments.
  • Fab and/or scFv expression libraries can be constructed to allow rapid identification of fragments having the desired specificity to NGAL or to SERPINA3.
  • phage display of antibodies may be used.
  • single-chain Fv (scFv) or Fab fragments are expressed on the surface of a suitable bacteriophage, e. g., M13.
  • spleen cells of a suitable host e. g., mouse
  • a suitable host e. g., mouse
  • the coding regions of the VL and VH chains are obtained from those cells that are producing the desired antibody against the protein. These coding regions are then fused to a terminus of a phage sequence.
  • a suitable carrier e. g., bacteria
  • the phage displays the antibody fragment.
  • Phage display of antibodies may also be provided by combinatorial methods known to those skilled in the art.
  • Antibody fragments displayed by a phage may then be used as part of an immunoassay.
  • the binding partner may be an aptamer.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition.
  • Aptamers are oligonucleotide or oligopeptide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library.
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence.
  • binding partners of the invention such as antibodies or aptamers, may be labelled with a detectable molecule or substance, such as a fluorescent molecule, a radioactive molecule or any others labels known in the art.
  • a detectable molecule or substance such as a fluorescent molecule, a radioactive molecule or any others labels known in the art.
  • Labels are known in the art that generally provide (either directly or indirectly) a signal.
  • the term "labelled", with regard to the antibody is intended to encompass direct labelling of the antibody or aptamer by coupling (i.e., physically linking) a detectable substance, such as a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5)) to the antibody or aptamer, as well as indirect labelling of the probe or antibody by reactivity with a detectable substance.
  • a detectable substance such as a radioactive agent or a fluorophore (e.g. fluorescein isothiocyanate (FITC) or phycoerythrin (PE) or Indocyanine (Cy5))
  • FITC fluorescein isothiocyanate
  • PE phycoerythrin
  • Indocyanine Indocyanine
  • An antibody or aptamer of the invention may be labelled with a radioactive molecule by any method known in the art.
  • Solid supports which can be used in the practice of the invention include substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • substrates such as nitrocellulose (e. g., in membrane or microtiter well form); polyvinylchloride (e. g., sheets or microtiter wells); polystyrene latex (e.g., beads or microtiter plates); polyvinylidine fluoride; diazotized paper; nylon membranes; activated beads, magnetically responsive beads, and the like.
  • the concentration of PTGDS may be measured by using standard immunodiagnostic techniques, including immunoassays such as competition, direct reaction, or sandwich type assays.
  • immunoassays such as competition, direct reaction, or sandwich type assays.
  • assays include, but are not limited to, agglutination tests; enzyme-labelled and mediated immunoassays, such as ELISAs; biotin/avidin type assays; radioimmunoassays; Immunoelectrophoresis; immunoprecipitation.
  • an ELISA method can be used, wherein the wells of a microtiter plate are coated with a set of antibodies which recognize said PTGDS. A biological sample containing or suspected of containing said PTGDS is then added to the coated wells. After a period of incubation sufficient to allow the formation of antibody-antigen complexes, the plate(s) can be washed to remove unbound moieties and a detectably labelled secondary binding molecule added. The secondary binding molecule is allowed to react with any captured sample marker protein, the plate washed and the presence of the secondary binding molecule detected using methods well known in the art.
  • Measuring the concentration of the PTGDS protein may also include separation of the compounds: centrifugation based on the compound's molecular weight; electrophoresis based on mass and charge; HPLC based on hydrophobicity; size exclusion chromatography based on size; and solid-phase affinity based on the compound's affinity for the particular solid-phase that is used.
  • said PTGDS may be identified based on the known "separation profile" e. g., retention time, for that compound and measured using standard techniques.
  • the separated compounds may be detected and measured by, for example, a mass spectrometer.
  • a reference value can be relative to a number or value derived from population studies, including without limitation, such subjects having similar body mass index, total cholesterol levels, LDL/HDL levels, systolic or diastolic blood pressure, subjects of the same or similar age range, subjects in the same or similar ethnic group, and subjects having the same severity of cirrhosis.
  • Such predetermined reference values can be derived from statistical analyses and/or risk prediction data of populations obtained from mathematical algorithms and computed indices of metabolic syndrome.
  • the predetermined reference values are derived from the level of PTGDS in a control sample derived from one or more subjects who were not subjected to obesity or metabolic syndrome.
  • the levels of PTGDS in a subject having mineralocorticoid receptor activation in the adipose tissue is deemed to be higher than the reference value obtained from the general population or from healthy subjects.
  • the expression level of PTGDS is deemed to be higher than the predetermined reference value obtained from the general population or from healthy subjects if the ratio of the expression level of PTGDS to that of said predetermined reference value is higher than 1.2, preferably 1.5, even more preferably 2, even more preferably 5, 10 or 20.
  • the method for assessing mineralocorticoid receptor activation in the adipose tissue according to the invention may find in various applications, In particular, the method of the present invention is particularly suitable for the treatment of subjects suffering from obesity or metabolic syndrome. Even more particularly, mineralocorticoid receptor antagonists have been suggested as beneficial for the treatment of metabolic syndrome. However, up to now, it was not possible to discriminate subjects that could benefit from such a treatment. Administration of a MR antagonist in a subject may be accompanied with serious adverse side effects such as hyperkalemia and therefore it is highly desirable to clearly identify subjects suffering from metabolic syndrome that could benefit of a treatment with a MR antagonist.
  • the present invention relates to a method for treating at least one metabolic derangement selected from the group consisting of abdominal obesity, total body weight gain, hypertension, hypertriglyceridemia, dyslipidemia, glucose intolerance, and insulin resistance in a subject suffering from metabolic syndrome comprising the steps of i) determining the expression level of PTGDS in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering the subject with a therapeutically effective amount of a mmeralocorticoid receptor antagonist or an inhibitor of mmeralocorticoid receptor gene expression when the expression level determined at step i) is higher than the predetermined reference value.
  • the present invention relates to a method for simultaneously reducing abdominal obesity, total body weight gain, hypertriglyceridemia, dyslipidemia, glucose intolerance, and insulin resistance associated with metabolic syndrome in a subject in need thereof comprising the steps of i) determining the expression level of PTGDS in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering the subject with a therapeutically effective amount of a mmeralocorticoid receptor antagonist or an inhibitor of mmeralocorticoid receptor gene expression when the expression level determined at step i) is higher than the predetermined reference value.
  • the present invention relates to a method for treating metabolic syndrome in a subject in need thereof comprising the steps of i) determining the expression level of PTGDS in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering the subject with a therapeutically effective amount of a mmeralocorticoid receptor antagonist when the expression level determined at step i) is higher than the predetermined reference value.
  • MR antagonist has its general meaning in the art.
  • the MR antagonistic of a compound may be determined using various methods as described in J, Souque A, Wurtz JM, Moras D, Rafestin-Oblin ME. Mol Endocrinol. 2000 Aug;14(8): 1210- 21; Fagart J, Seguin C, Pinon GM, Rafestin-Oblin ME. Mol Pharmacol. 2005 May;67(5): 1714-22 or Hellal-Levy C, Fagart J, Souque A, Wurtz JM, Moras D, Rafestin- Oblin ME. Mol Endocrinol. 2000 Aug;14(8): 1210-21.
  • mmeralocorticoid receptor antagonists are typically selective for the mineralocorticoid receptor as compared with the related receptors such as androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, thyroid hormone receptors, peroxisome proliferator-activated receptors, retinoic acid receptor, farnesoid x receptor, pregnane x receptor, liver X receptor, vitamin D receptor, retinoid x receptor and the constitutive androstane receptor.
  • the related receptors such as androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, thyroid hormone receptors, peroxisome proliferator-activated receptors, retinoic acid receptor, farnesoid x receptor, pregnane x receptor, liver X receptor, vitamin D receptor, retinoid x receptor and the constitutive androstane receptor.
  • MR antagonists constitute a class o pharmacological compounds that are well known by the skilled artisan.
  • the mineralocorticoid receptor antagonists according to the invention generally are spirolactone-type steroidal compounds.
  • the term "spirolactone-type" is intended to characterize a structure comprising a lactone moiety attached to a steroid nucleus, typically at the steroid "D" ring, through a spiro bond configuration.
  • a subclass of spirolactone-type mineralocorticoid receptor antagonist compounds consists of epoxy-steroidal mineralocorticoid receptor antagonist compounds such as eplerenone.
  • Another subclass of spirolactone-type antagonist compounds consists of non-epoxy-steroidal mineralocorticoid receptor antagonist compounds such as spironolactone.
  • the epoxy-steroidal mineralocorticoid receptor antagonist compounds used in the method of the present invention generally have a steroidal nucleus substituted with an epoxy- type moiety.
  • epoxy-type moiety is intended to embrace any moiety characterized in having an oxygen atom as a bridge between two carbon atoms.
  • steroidal as used in the phrase “epoxy-steroidal,” denotes a nucleus provided by a cyclopenteno-phenanthrene moiety, having the conventional "A", "B", “C”, and “D” rings.
  • the epoxy-type moiety may be attached to the cyclop entenophenanthrene nucleus at any attachable or substitutable positions, that is, fused to one of the rings of the steroidal nucleus or the moiety may be substituted on a ring member of the ring system.
  • the phrase "epoxy-steroidal" is intended to embrace a steroidal nucleus having one or a plurality of epoxy-type moieties attached thereto.
  • Epoxy-steroidal mineralocorticoid receptor antagonists suitable for use in the present methods include a family of compounds having an epoxy moiety fused to the "C" ring of the steroidal nucleus. Examples include 20-spiroxane compounds characterized by the presence of a 9a, 1 la-substituted epoxy moiety, such as:
  • a particular benefit of using epoxy-steroidal mmeralocorticoid receptor antagonists, as exemplified by eplerenone, is the high selectivity of this group of mmeralocorticoid receptor antagonists for the mmeralocorticoid receptor.
  • the superior selectivity of eplerenone results in a reduction in side effects that can be caused by mmeralocorticoid receptor antagonists that exhibit non-selective binding to related receptors, such as androgen or progesterone receptors.
  • These epoxy steroids may be prepared by procedures described in Grab et al, U.S. Pat. No. 4,559,332. Additional processes for the preparation of 9, 11-epoxy steroidal compounds and their salts are disclosed in Ng et al, WO97/21720 and Ng et al, W098/25948.
  • Eplerenone is a mineralocorticoid receptor antagonist and has a higher selectivity for mineralocorticoid receptors than does, for example, spironolactone. Selection of eplerenone as the mineralocorticoid receptor antagonist in the present method would be beneficial to reduce certain side-effects such as gynecomastia that occur with use of mineralocorticoid receptor antagonists having less specificity.
  • Non-epoxy-steroidal mineralocorticoid receptor antagonists suitable for use in the present methods include a family of spirolactone-type compounds defined by Formula I:
  • Lower alkyl residues include branched and unbranched groups, for example, methyl, ethyl and n-propyl.
  • Rl is Cl-3-alkyl or CI -3 acyl and R2 is H or Cl-3-alkyl.
  • R is lower alkyl, examples of which include lower alkyl groups of methyl, ethyl, propyl and butyl.
  • Specific compounds of interest include:
  • ⁇ ' is selected from the group consisting of ethylene, vinylene and (lower alkanoyl)thioethylene radicals
  • ⁇ " is selected from the group consisting of ethylene, vinylene, (lower alkanoyl)thioethylene and (lower alkanoyl)thiopropylene radicals
  • R is a methyl radical except when E and ⁇ " are ethylene and (lower alkanoyl) thioethylene radicals, respectively, in which case R is selected from the group consisting of hydrogen and methyl radicals
  • the selection of E' and ⁇ " is such that at least one (lower alkanoyl)thio radical is present.
  • Another compound of Formula V is l-acetylthio-17a-(2-carboxyethyl)-17P-hydroxy- androst-4-en-3-one lactone.
  • Exemplary compounds within Formula VI include the following: 7a-acetylthio- 17a-(2-carboxyethyl)- 17P-hydroxy-androst-4-en-3-one
  • alkyl is intended to embrace linear and branched alkyl radicals containing one to about eight carbons.
  • (lower alkanoyl)thio embraces
  • drospirenone (6R-(6 a , 7 a , 8 /3 , 9 a , 10 /3 , 13 /3 , 14 ⁇ , 15 ⁇ , 16 a , 17 /3 ))-l , 3' , 4' , 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 20, 21-hexadecahydro-lO, 13-dimethylspiro [17H- dicyclopropa(6,7: 15, 16)cyclopenta(a)phenanthrene-17,2 (5 f tJ -far )-3,5' (2H)-dione, CAS registration number 67392-87-4.
  • Methods to make and use drospirenone are described in patent GB 1550568 1979, priority DE 2652761 1976.
  • Crystalline forms that are easily handled, reproducible in form, easily prepared, stable, and which are non-hygroscopic have been identified for the mineralocorticoid receptor antagonist eplerenone. These include Form H, Form L, various crystalline solvates and amorphous eplerenone. These forms, methods to make these forms, and use of these forms in preparing compositions and medicaments, are disclosed in Barton et al, WO 01/41535 and Barton et al., WO 01/42272 both incorporated herein in their entirety.
  • Mineralocorticoid receptor antagonists according to the invention may also be nonsteroidal.
  • Arhancet el al. disclose other class of non-steroidal MR antagonists (Arhancet GB, Woodard SS, Dietz JD, Garland DJ, Wagner GM, Iyanar K, Collins JT, Blinn JR, Numann RE, Hu X, Huang HC. Stereochemical Requirements for the Mineralocorticoid Receptor Antagonist Activity of Dihydropyridines. J Med Chem. 2010 Apr 21).
  • non-steroidal mineralocorticoid receptor antagonists include but are not limited to those described in US 20090163472 WO2004052847, WO 2008053300 WO2008104306, WO2007025604, WO201264631 , WO2008126831 , WO2012008435, WO2010104721 , WO200985584, WO200978934, WO20081 18319, WO200917190, WO200789034, WO2012022121 , WO2012022120, WO201 1 141848 and WO200777961 that are hereby incorporated by reference into the present disclosure.
  • the mineralocorticoid receptor antagonist is selected from the group consisting of:
  • an “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • said inhibitor of gene expression is a siR A, an antisense oligonucleotide or a ribozyme.
  • anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of mineralocorticoid receptor mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of mineralocorticoid receptor, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding mineralocorticoid receptor can be synthesized, e.g., by conventional phosphodiester techniques.
  • Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • Small inhibitory RNAs can also function as inhibitors of expression for use in the present invention, mineralocorticoid receptor gene expression can be reduced by contacting a subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that mineralocorticoid receptor gene expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Antisense oligonucleotides, siRNAs, shRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector” is any vehicle capable of facilitating the transfer of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid to the cells and typically cells expressing mineralocorticoid receptor. Typically, the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide, siRNA, shRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus; adenovirus, adeno-associated virus; SV40-type viruses; polyoma viruses; Epstein-Barr viruses; papilloma viruses; herpes virus; vaccinia virus; polio virus; and R A virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rous sarcoma virus
  • adenovirus adeno-associated virus
  • the active ingredients of the invention are administered to the subject in a therapeutically effective amount.
  • a therapeutically effective amount is meant a sufficient amount of the active ingredient for treating or reducing the symptoms at reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the active ingredients; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the active ingredients of the invention e.g. the MR antagonist or the inhibitor of expression
  • pharmaceutically acceptable excipients e.g. the MR antagonist or the inhibitor of expression
  • sustained-release matrices such as biodegradable polymers
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi- so lid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • the active ingredients of the invention can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the present invention relates to a method to a method for predicting whether a subject suffering from metabolic syndrome is responsive with a treatment with a MR antagonist or an inhibitor of MR gene expression comprising the steps of i) determining the level expression of PTGDS before the treatment, ii) determining the level expression of PTGDS after the treatment, iii) comparing the level determined at step ii) with level determined at step i) and iv) concluding that the subject is responsive to the treatment when the level determined at step ii) is lower than the level determined at step i).
  • the invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 MR is overexpressed in adipose tissues from db/db mice.
  • Adipocyte aP2-rtTA - Tet-O-transgene mouse model allow the conditional expression of a chosen transgene in adipocytes in vivo.
  • A. Adipocyte-aP2- rtTA - Tet-O-transgene mouse, i.e. Adipo-LacZ and Adipo-MROE, are double transgenic mouse model that results from the crossing of two different mono transgenic mouse model. The first which expresses viral transcription factor rtTA under the control of the adipocyte- specific promoter of aP2 gene, and the second which brings the genetic construct composed of rtTA paired promoter, i.e.
  • Tet-O Tet-O
  • a chosen transgene i.e., LacZ and hMR
  • rtTA becomes activated and it binds its promoter tet-O, which finally starts transgene expression in aP2 expressing cells.
  • Adipo-lacZ mice conditionally express bacterial ⁇ -galactosidase in adipocytes in vivo. Thirty minutes of X-Gal solution exposure of fresh organs taken from Adipo-lacZ mice results immediately in an intense blue staining of only adipose tissues.
  • PTGDS Prostaglandin D2 Synthase
  • adipo-MROE mice Increased of PTGDS gene expression in adipo-MROE mice: significant PTGDS increase was confirmed in VAT of another series of adipo-MROE mice, as compared to control littermates ( Figure 5 A).
  • Twenty- four hours aldosterone (Aldo, 10 ⁇ 8 M) stimulation in a steroid-free medium increases PTGDS mRNA expression level in differentiated primary cultured adipocytes derived adipo-MROE SAT ( Figure 5B) and in differentiated 3T3-L1 adipocytes ( Figure 5C).
  • PTGDS levels are also increased in the supernatant of 3T3-L1 cells upon treatment with Aldo (Aldo, 10 ⁇ 8 M), an effect prevented by MRA (Figure 5F).
  • Aldo Aldo
  • MRA MRA
  • Dexamethasone Dexamethasone (Dexa, 10 ⁇ 8 M) has not effect of PTGDS levels (Figure 5F).
  • FIG. 6 The Prostaglandin D2 Synthase (PTGDS) blunted the effects of Aldo in adipocytes.
  • A Effect of PTGDS antagonism (AT-56) on aldo-induced adipogenesis in 3T3- Ll cells.
  • B Effect of PTGDS antagonism (AT-56) on aldo-induced PPARg2 expression in 3T3-L1 cells.
  • C Effect of PTGDS antagonism (AT-56) on aldo-induced AP2 expression in 3T3-L1 cells.
  • D Effect of PTGDS antagonism (AT-56) on aldo-induced Leptin expression in 3T3-L1 cells.
  • E Effect of PTGDS antagonism (AT-56) on aldo-induced Leptin expression in 3T3-L1 cells.
  • PTGDS is a mineralocorticoid receptor target in adipose tissues from obese db/db mice.
  • PTGDS mRNA levels are increased in VAT of obese mice compared to their control littermates (db/-) ( Figure 7A).
  • PTGDS is a target of MR activation in human adipose tissue.
  • Aldosterone (Aldo, 10 "8 M) stimulation increased PTGDS mRNA expression level in the differentiated SW872 human adipocytes (Figure 8A).
  • MR expression level was in VAT versus SAT from obese patients ( Figure 8B).
  • VAT also showed higher expression level of PTGDS mRNA (2.5 fold) as compared to SAT in these patients ( Figure 8C).
  • FIG. 9 PTGDS and MR are also correlated in adipose tissues from obese patients.
  • Adipo-MROE mice displayed weight gain and altered glucose metabolism.
  • Insulin ng/mL 1.0 ⁇ 0.1 1.5 ⁇ 0.2* 0.9 ⁇ 0.2 2.35 ⁇ 0.4
  • Triglycerides (mg/dL) 84.0 ⁇ 5.0 1 18.0 ⁇ 17* 187 ⁇ 29 181 ⁇ 24
  • Glucose metabolism was tested by fasting intraperitoneal insulin tolerance test (ITT,) and glucose tolerance test (GTT).
  • ITT intraperitoneal insulin tolerance test
  • GTT glucose tolerance test
  • Adipo-MROE mice showed weaker physiological response to insulin as well as glucose stress charges ( Figure 3D and 3E).
  • the analysis of insulin curves during GTT which take into account the endogenous release of insulin to counteract glucose charge, revealed a higher peak at minute 30 in Adipo-MR mice compared to their Control-MR littermates ( Figure 3F). This suggests that Adipo-MR animals need to secrete more insulin to normalize glycaemia.
  • increased MR expression in adipocytes led to insulin resistance and increased fat mass, even when mice are fed a standard diet.
  • Adipo-MROE mice Upon High Fat diet challenge, Adipo-MROE mice showed a higher body mass gain as compared compared to their Control-MR litteramates (Figure 4A). This difference kept significantly growing for at least 14 weeks with HFD. Important impairment in insulin response was clearly impaired in both groups of mice when challenged with 0.05 U/ml of insulin. Adipo-MROE mice displayedvirtually no response to insulin ( Figure 4B). Increasing the dose for insulin challenge (0.1 U/ml) allowed insulin response which was impaired in Adipo-MROE mice when compared to Control littermates ( Figure 4C). GTT was not statistically different between Control-MR and Adipo-MROE mice ( Figure 4D). In conclusion increased MR expression in adipocyte sensitize increased insulin resistance induced by HFD.
  • the Prostaglandin D2 Synthase (PTGDS) is a novel MR target in adipose tissue.
  • PTGDS lipocalin-like prostaglandin D2 synthase
  • aldosterone (Aldo, 10 "8 M) stimulation in a steroid- free medium increases PTGDS mRNA expression level in in differentiated primary cultured adipocytes derived adipo-MROE SAT ( Figure 5B) and in differentiated 3T3-L1 adipocytes (Figure 5C) This increase is fully prevented by co-incubation with the MR antagonist spironolactone (MRA, 10 "6 M) ( Figure 5B-C).
  • Dexamethasone (Dexa, 10 "8 M) a specific glucocorticoid receptor agonist did not affect PTGDS mRNA levels in 3T3-L1 cells ( Figure 5C).
  • PTGDS is a secreted protein.
  • Plasma levels was increased in the plasma of Mice overexpressing MR in adipoMROE mice ( Figure 5D) as well as in adipocyte-conditionned medium (ACM) from adipoMROE EVAT ( Figure 5 E).
  • PTGDS levels are also increased in the supernatant of 3T3-L1 cells upon treatment with Aldo (Aldo, 10 "8 M), an effect prevented by MRA ( Figure 5F).
  • Aldo Aldo, 10 "8 M
  • PSGDS Prostaglandin D2 Synthase
  • AT56 is a competitive antagonist of PTGDS.
  • PTGDS is a mineralocorticoid receptor target in adipose tissues from obese db/db mice.
  • PTGDS is a target of MR activation in human adipose tissue.
  • Aldosterone (Aldo, 10 "8 M) stimulation increased PTGDS mRNA expression level in the differentiated SW872 human adipocytes ( Figure 8A). This increase is prevented by coincubation of aldosterone with the MR antagonist spironolactone (MRA, 10 "6 M) ( Figure 8 A).
  • MR antagonism is able to block adipocyte differentiation ex vivo also in human primary preadipocytes from different fat depots, giving the MR a relevant role in the pathophysiology of adipose dysfunction in humans.
  • aldosterone could also acts on its receptor in adipose tissue. Since aldosterone is highly lipophylic and less prone to plasma protein binding, it may accumulate in adipocytes and activates the MR. Moreover, it has been recently demonstrated that adipocytes produce aldosterone, leading to local paracrine MR activation in adipose tissue. In the present study we used aldo in the ex vivo experiments in order to avoid confounding effects of GR activation when using glucocorticoids.

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Abstract

La présente invention concerne des méthodes d'évaluation de l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux d'un patient. En particulier, la présente invention concerne une méthode d'évaluation de l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux d'un patient comprenant les étapes consistant i) à déterminer le niveau d'expression de PTGDS dans un échantillon prélevé chez le patient, ii) à comparer le niveau d'expression déterminé à l'étape i) avec une valeur de référence prédéterminée et iii) à conclure en l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux du patient lorsque le niveau d'expression déterminé à l'étape i) est supérieur à la valeur de référence prédéterminée. L'invention concerne également l'utilisation d'antagonistes du récepteur des minéralocorticoïdes dans le traitement de troubles métaboliques, par exemple le syndrome métabolique ou l'obésité.
PCT/EP2015/065550 2014-07-09 2015-07-08 Méthodes d'évaluation de l'activation du récepteur des minéralocorticoïdes dans le tissu adipeux d'un patient, et de traitement du syndrome métabolique Ceased WO2016005424A1 (fr)

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EP1224861A1 (fr) * 1999-10-05 2002-07-24 Japan Science and Technology Corporation Animal exprimant un gene humain a grande echelle et procede de test utilisant ledit animal
WO2010046411A1 (fr) * 2008-10-24 2010-04-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Biomarqueurs de l’activation du récepteur des minéralocorticoïdes

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