WO2003105900A1 - Regulation de spla2giia - Google Patents

Regulation de spla2giia Download PDF

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Publication number
WO2003105900A1
WO2003105900A1 PCT/EP2003/005826 EP0305826W WO03105900A1 WO 2003105900 A1 WO2003105900 A1 WO 2003105900A1 EP 0305826 W EP0305826 W EP 0305826W WO 03105900 A1 WO03105900 A1 WO 03105900A1
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WO
WIPO (PCT)
Prior art keywords
spla2giia
expression
diseases
rats
shr
Prior art date
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PCT/EP2003/005826
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German (de)
English (en)
Inventor
Birgit Andree
Peter Ellinghaus
Raimund Kast
Original Assignee
Bayer Aktiengesellschaft
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Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU2003236684A priority Critical patent/AU2003236684A1/en
Publication of WO2003105900A1 publication Critical patent/WO2003105900A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/005—Enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • the invention relates to the use of sPLA2G ⁇ A antagonists / inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of coronary heart diseases, in particular stable and unstable angina pectoris, acute myocardial infarction, myocardial infarction prophylaxis, heart failure, as well as high blood pressure and the consequences of atheros, as well as atherosity, as well as atherosclerosis. Kidney diseases, especially kidney failure, inflammatory diseases, erectile dysfunction and to prevent sudden cardiac death.
  • the heart as an incessantly working hollow muscle, needs a particularly intensive supply of oxygen to cover its energy requirements.
  • Supply disorders therefore primarily concern oxygen transport, which can be insufficient if the blood circulation is less adaptable.
  • An increase in oxygen consumption can only be covered by an increase in cardiac blood flow.
  • heart failure With coronary heart diseases such as stable and unstable angina pectoris, heart failure, myocardial infarction, sudden cardiac death, as well as the consequences of atherosclerosis, adequate blood circulation to parts of the heart tissue is no longer guaranteed and tissue ischemia occurs, which leads to ecrosis and apoptosis in the affected areas. This leads to myocardial dysfunction, which can develop into heart failure.
  • Substances and processes that lead to an increase in coronary flow in the heart and / or to a decrease in blood pressure can be used therapeutically
  • the DNA sequence coding for the human sPLA2GHA is shown in the sequence listing in SEQ ID NO: 1.
  • the amino acid sequence of the human sPLA2GIIA is shown in SEQ ID NO: 2 of the sequence listing.
  • the sPLA2GHA in the mouse is expressed in the intestine and in the prostate (2).
  • the expression of sPLA2GIIA in humans is described in the heart, placenta, liver, skeletal muscle, prostate and intestine (3).
  • sPLA2GIIA plays a role in the development of various inflammatory diseases.
  • the expression of sPLA2GIIA can be induced by cytokines and bacterial toxins at the transcriptional level.
  • this mechanism does not appear to apply to all cell types. In rat vascular smooth muscle cells, for example, it was shown that the
  • the present invention therefore relates to the use of sPLA2GIIA inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of the following diseases: coronary heart diseases, in particular stable and unstable angina pectoris, acute myocardial infarction, myocardial infarction prophylaxis, sudden cardiac death, heart failure, as well as high blood pressure and the consequences of atherosclerosis, as well as vascular diseases, diseases of the kidneys, in particular kidney failure, inflammatory diseases and erectile dysfunction.
  • coronary heart diseases in particular stable and unstable angina pectoris, acute myocardial infarction, myocardial infarction prophylaxis, sudden cardiac death, heart failure, as well as high blood pressure and the consequences of atherosclerosis, as well as vascular diseases, diseases of the kidneys, in particular kidney failure, inflammatory diseases and erectile dysfunction.
  • Antagonists / inhibitors in the sense of the invention are all substances which cause an inhibition of the biological activity of the sPLA2GIIA.
  • Particularly preferred antagonists / inhibitors are nucleic acids including “locked nucleic acids”, “Peptide nucleic acids” and “Spiegelmers", proteins including antibodies and low-molecular substances, very particularly preferred antagonists / inhibitors are low-molecular substances.
  • the inhibition can e.g. be measured in the sPLA2GIIA inhibition test described below.
  • sPLA2GIIA antagonists inhibitors are preferred in the specified below * sPLA2GIIA inhibition assay with an IC 5 o of 1 uM, preferably with an IC 5 o of less than 0.1 uM inhibit.
  • the sPLA2GIIA antagonists / inhibitors according to the invention are preferably unable to cross the blood / brain barrier and act systemically and not centrally.
  • ⁇ SD The mean ⁇ SD of the expression of the sPLA2GIIA relative to ⁇ 2-microglobulin (rE) in the aortas of different rat strains is shown.
  • the mean ⁇ SD is calculated from the specified number of animals per group.
  • the following rat strains were examined: spontaneously hypertensive rats (SHR), spontaneously hypertensive “stroke prone” rats (SHR-SP) with Wistar-Kyoto rats (WKY) as controls, transgenic renin rats (TGR) with Sprague-Dawley Rats (SD) as
  • Control and salt-sensitive Dahl rats (DahlS) with salt-resistant Dahl rats (DahlR) as a control. Two times are used for the analyzes for the SHR, SHR-SP and TGR rats. There are animals at the age of 5 weeks (young) and at the age of 15-20 weeks for the SHR and SHR-SP rats and at the age of 10 weeks for the TGR rats (old) with the corresponding controls of the same age analyzed.
  • salt-sensitive Dahl rats high blood pressure induced by salt pollution. Animals 7 weeks old are fed for 4 weeks with food containing 8% NaCl (DahlS + NaCl).
  • DahlR rats with salt exposure (DahlR + NaCl) and DahlS and DahlR rats of the same age without salt exposure serve as controls.
  • Expression analysis of the sPLA2GIIA in the rat shows that in all hypertensive animals (SHR old, SHR-SP old, TGR old, DahlS + NaCl) the expression of the sPLA2GIIA in the aorta is increased in comparison to the controls.
  • the results are tabulated below (mean value of the relative expression rE, standard deviation SD, mean value of the Ct values for sPLA2GIIA and ⁇ 2-microglobulin).
  • sPLA2GIIA The expression of the sPLA2GIIA is shown relative to ß-actin (rE) in heart samples from four patients (Patientl-4), involved in the implantation of the LVAD (impl) and in
  • Explantation of the LVAD can be taken after recovery.
  • patients 2, 3 and 4 a reduction in the mRNA for the sPLA2GIIA at the time of explantation compared to the time of implantation can be observed.
  • the results are shown in a table (mean value of the relative expression rE from a triple determination, standard deviation SD, mean value of the Ct values for SPLA2GEA and beta-actin).
  • the expression of SPLA2GHA relative to ⁇ -actin is shown in various human tissues.
  • the human tissue profile shows that the sPl_A2GIIA is expressed far more weakly in the heart than in the vessels, especially the coronary artery.
  • l heart
  • 2 coronary artery
  • 3 radial artery
  • 4 saphenous vein
  • 5 fetal aorta
  • 6 aorta
  • 7 brain
  • 8 spinal cord
  • 9 liver
  • 10 skeletal muscle
  • the relative expression of the sPLA2GIIA in tissues from the rat and in human tissues is determined by quantifying the mRNA using the real-time polymerase chain reaction (5). Compared to classic PCR, the
  • Real-time PCR has the advantage of more precise quantification by introducing an additional, fluorescence-labeled oligonucleotide.
  • This so-called probe contains the fluorescent dye FAM (6-carboy-fluorescein) at the 5 'end and the fluorescent quencher TAMRA (6-carboxy-tetramethylrhodamine) at the 3' end.
  • FAM fluorescent dye
  • TAMRA fluorescent quencher
  • the exonuclease activity of the Taq polymerase cleaves the fluorescent dye FAM from the probe and thereby obtains the previously quenched fluorescent signal.
  • the number of cycles at which the fluorescence intensity is approx. 10 standard deviations above the background fluorescence is recorded as the so-called threshold value (Ct value).
  • RNAeasy RNA is used as the starting material for the PCR.
  • small pieces approximately (approx. 0.5 g) of explanted hearts from patients with dilated cardiomyopathy (obtained from the German Heart Center Berlin) and the total RNA from them are extracted using RNAeasy
  • RNA is also isolated from the prepared aortic pieces. 1 ⁇ g total RNA per tissue is used to remove contaminations with genomic DNA with 1 unit DNase I (Invitrogen) for 15 min at room temperature. Dnase I is inactivated by adding 1 ⁇ l EDTA (25 mM) and then heating to 65 ° C. (10 min).
  • DNase I Invitrogen
  • the cDNA synthesis is then carried out in the same reaction mixture in accordance with the instructions for the “SUPERSCRIPT-II RT cDNA synthesis kit” (from Invitrogen) and the reaction volume is made up to 200 ⁇ l with distilled water.
  • each 5 ⁇ l of the diluted cDNA solution is 7.5 ⁇ l mixture of Primer and probe as well as 12.5 ⁇ l TaqMan reaction solution (qPCR master mix, from Eurogentec).
  • the final concentration of each primer is 300 nM, that of the probe 150 nM.
  • the sequence of the "forward" and “reverse” primer for the SPLA2GÜA of the rat is: 5'-GACTCATGACTGTTGTTACAACCGT-3 '(SEQ ID NO: 6) or 5'-CGGTAGGAGAACTTGTAGGTCAGAA-3' (SEQ ID NO: 7) , the sequence of the. fluorescent probe 5'-6FAM-
  • the sequence of the "forward" and “reverse” primer for the human sPLA2GIIA is: 5'-CCCATGGGAATTTGGTGAAT-3 '(SEQ ID NO: 3) and 5'-CATAACTGAGTGCGGCTTCCT-3' (SEQ ID NO: 4), the sequence of the fluorescent probe 5'-6FAM-TCCACAGAATGATCAAGTTGACGACAGGA-TAMRA-3 '(SEQ ID NO: 5).
  • the PCR is carried out on an ABI-Prism-SDS-7700 device (from Applied Biosystems) according to the manufacturer's instructions. 40 cycles are carried out.
  • the Ct value (see above) which is obtained for the sPLA2GIIA for each tissue corresponds to the cycle in which the fluorescence intensity of the released probe lies approximately 10 standard deviations above the background signal.
  • the expression of a so-called “household gene” is also analyzed in all examined tissues. This should be expressed approximately equally strongly in all tissues.
  • Human ⁇ is used for normalizing sPLA2GILA expression in human tissues
  • the sequence of the "forward” or “reverse” primer for human ⁇ -actin is 5'-TCCACCTTCCAGCAGATGTG-3 '(SEQ ID NO: 9), and 5'-CTAGAAGCATTTGCGGTGGAC-3' (SEQ ID NO : 10), the sequence of the probe 5'-
  • ⁇ 2-microglobulin is used for this.
  • the sequence of the "forward” or “reverse” primer for ⁇ 2-microglobulin from the rat is 5'-TGCCATTCAGAAAACTCCCC-3 '(SEQ ID NO: 12), and 5'-GGAAGTTGGGCTTCCCATTC-3' (SEQ ID NO: 13 ) the sequence of the probe 5'-6FAM- TCAAGTGTACTCTCGCCATCCACCGG- TAMRA-3 '(SEQ ID NO: 14).
  • the evaluation of the data is carried out as follows: for the graphic representation of the tissue distribution of the sPLA2GIIA, the dCt value is calculated for each tissue.
  • the dCt value is the difference between the Ct value for the sPLAG2A and the Ct value of the household gene in the respective tissue. This value becomes a relative according to the following formula
  • the value X is an assumed average value for the respective household gene
  • the relative expression is set to zero.
  • SHR spontaneously hypertensive rats
  • SHR-SP spontaneously hypertensive "stroke prone" rats
  • WKY Wistar-Kyoto rats
  • TGR transgenic renin rats
  • SD Sprague-Dawley rats
  • DahlS salt-sensitive Dahl rats
  • DahlR salt-resistant Dahl rats
  • the human tissue profile shows that sPLAG2A is expressed much more weakly in the heart than in the vessels, especially the coronary artery ( Figure 3).
  • sPLA2GIIA The inhibition of sPLA2GIIA is measured in a chromogenic assay with mixed substrate micelles (Reynolds L.J. et al; Analysis of human synovial fluid phospholipase A2 on short chain phosphatidylcholine-mixed micelles: Development of a spectrophotometric assay suitable for a microtiterplate reader (6).
  • the substrate solution is first pipetted onto the polystyrene microtiter plate (0.2 ml per well), then 5 ⁇ l DTNB (5.5'-dithiobis (2-nitrobenzoic acid) (33 mM in H2O, pH 7.5) is added one
  • the IC o value corresponds to the substance concentration at which the sPLA2GIIA activity is inhibited by 50%.
  • the in vzvo test of the sPLA2GIIA antagonists / inhibitors is carried out in hypertonic rat strains (SHR-SP, SHR, TGR). There is also a mouse strain in which the sPLA2GIIA is overexpressed (7). This mouse strain serves on the one hand as another in vivo test system and on the other hand for further testing of the disease hypothesis. It can be expected that an increased blood pressure due to the overexpression of the sPLA2GIIA can be observed in this mouse strain.
  • the sPLA2GIIA antagonists / inhibitors can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally, intravenously or parenterally, in particular orally or intravenously. However, it can also be done by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the skin. In general, it has been found to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.005 to 3 mg / kg body weight for oral use in order to achieve effective results.
  • ANP atrial natriuretic peptide
  • BNP natriuretic peptide, brain-specific (natriuretic peptide, brain type)
  • DCM dilated cardiomyopathy expl: explantation impl: implantation
  • LVAD mechanical left ventricular assist device (rE): relative expression

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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne l'utilisation d'antagonistes/inhibiteurs de sPLA2GIIA destinés à la production d'un médicament destiné au traitement et/ou à la prophylaxie de cardiopathies ischémiques, notamment l'angine de poitrine stable et instable, l'infarctus du myocarde aigu, la prophylaxie de l'infarctus du myocarde, une insuffisance cardiaque et une hypertension et les conséquences de l'athérosclérose ainsi que les vasculopathies, les maladies reinales, notamment l'insuffisance rénale, les maladies inflammatoires, les troubles de l'érection et l'empêchement de mort par arrêt cardiaque soudain.
PCT/EP2003/005826 2002-06-17 2003-06-04 Regulation de spla2giia WO2003105900A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003236684A AU2003236684A1 (en) 2002-06-17 2003-06-04 Regulation of secretory phospholipase a2 group iia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10226934A DE10226934A1 (de) 2002-06-17 2002-06-17 Regulation der sPLA2G2A
DE10226934.3 2002-06-17

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WO2003105900A1 true WO2003105900A1 (fr) 2003-12-24

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DE (1) DE10226934A1 (fr)
WO (1) WO2003105900A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011151527A1 (fr) * 2010-06-03 2011-12-08 Estaja Oy Méthode de préparation d'inhibiteurs peptidiques d'une enzyme activée par des lipides et peptides produits par cette méthode
WO2013067579A1 (fr) * 2011-11-07 2013-05-16 The University Of Queensland Molécules modulant l'adiposité et utilisations associées

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071118A1 (fr) * 1999-05-19 2000-11-30 Universite Paris 7 - Denis Diderot Composes inhibiteurs specifiques de la phospholipase a¿2?

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000071118A1 (fr) * 1999-05-19 2000-11-30 Universite Paris 7 - Denis Diderot Composes inhibiteurs specifiques de la phospholipase a¿2?

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
D.A. SIX ET AL.: "The expanding superfamily of phospholipase A2 enzymes: classification and characterization.", BIOCHIMICA ET BIOPHYSICA ACTA: MOLECULAR AND CELL BIOLOGY OF LIPIDS, vol. 1488, no. 1-2, 31 October 2000 (2000-10-31), pages 1 - 19, XP002258592 *
E. HURT-CAMEJO ET AL.: "Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries.", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 17, no. 2, February 1997 (1997-02-01), pages 300 - 309, XP008023538 *
E. HURT-CAMEJO ET AL.: "Phospholipase A2 in vascular disease.", CIRCULATION RESEARCH, vol. 89, no. 4, 17 August 2001 (2001-08-17), pages 298 - 304, XP002258590 *
E.D. MIHELICH ET AL.: "Structure-based design of a new class of anti-inflammatory drugs: secretory phospholipase A2 inhibitors, SPI.", BIOCHIMICA ET BIOPHYSICA ACTA: MOLECULAR AND CELL BIOLOGY OF LIPIDS, vol. 1441, no. 2-3, 23 November 1999 (1999-11-23), pages 223 - 228, XP002258589 *
K. KUGIYAMA ET AL.: "Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease.", CIRCULATION, vol. 100, no. 12, 12 September 1999 (1999-09-12), pages 1280 - 1284, XP002258591 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011151527A1 (fr) * 2010-06-03 2011-12-08 Estaja Oy Méthode de préparation d'inhibiteurs peptidiques d'une enzyme activée par des lipides et peptides produits par cette méthode
WO2013067579A1 (fr) * 2011-11-07 2013-05-16 The University Of Queensland Molécules modulant l'adiposité et utilisations associées

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AU2003236684A1 (en) 2003-12-31
DE10226934A1 (de) 2003-12-24

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