WO2018115083A1 - Méthode de traitement de maladies intestinales telles que le syndrome de l'intestin irritable (sii) - Google Patents

Méthode de traitement de maladies intestinales telles que le syndrome de l'intestin irritable (sii) Download PDF

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Publication number
WO2018115083A1
WO2018115083A1 PCT/EP2017/083743 EP2017083743W WO2018115083A1 WO 2018115083 A1 WO2018115083 A1 WO 2018115083A1 EP 2017083743 W EP2017083743 W EP 2017083743W WO 2018115083 A1 WO2018115083 A1 WO 2018115083A1
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trypsin
ibs
inhibitor
activity
bowel syndrome
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PCT/EP2017/083743
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English (en)
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Nathalie Vergnolle
Claire ROLLAND-FOURCADE
Céline DERAISON-MANUEL
Carla Cirillo
Alexandre DENADAI SOUZA
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paul Sabatier Toulouse Iii
Ecole Nationale Vétérinaire de Toulouse
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Publication of WO2018115083A1 publication Critical patent/WO2018115083A1/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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6427—Chymotrypsins (3.4.21.1; 3.4.21.2); Trypsin (3.4.21.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21004—Trypsin (3.4.21.4)

Definitions

  • Trypsin-3 was the only form of trypsin up-regulated in stimulated intestinal epithelial cells and in IBS patient tissues. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a Protease-Activated Receptor- 2-dependent mechanism. Trypsin-3 inhibitor
  • Trypsin-3 inhibitor (inhibitor of expression or of activity) may be used to treat gut diseases associated with intestinal permeability and visceral hypersensitivity.
  • the term “selectively blocks or inactivates” refers to a compound that preferentially binds to and blocks or inactivates Trypsin-3 with a greater affinity and potency, respectively, than its interaction with the other sub-types of the Trypsin family (Trypsin- 1 or Trypsin-2 for example).
  • Trypsin-3 inhibitor also refers to a compound that inhibits Trypsin-3 expression.
  • inhibitor of the TRYPSIN-3 activity is selected from the group consisting of antibodies, aptamers, polypeptides.
  • Figure 3 Intestinal epithelial cells up-regulate Trypsin-3 secretion in inflammatory condition and in IBS Mean fluorescence intensity for Trypsin-3- immunoreactivity quantified specifically in epithelial (Epcam-positive) cells in tissues from healthy controls or IBS patients. Data are expressed as mean ⁇ SEM and were analyzed by Student's t-test in A and C, and a one-way ANOVA followed by a Bonferroni post-test in B.
  • Caco-2 cells were grown to confluence as monolayers in Transwell plates (2x105 cells per well) (Corning)[15]. After 21 days in culture (transepithelial electrical resistance of 350 ⁇ cm2)[15], culture medium was replaced by OptiMEM (Life technologies) and cells incubated for 24 hours (h) before stimulation on apical and baso-lateral sides by LPS (50 ⁇ g/mL, Sigma), or by epinephrine (5nM, Sigma) on the basolateral side [16] for 2, 4, 6, 18 and 24h to mimic a stress condition in vitro. In a third set of experiments, Caco-2 monolayers were exposed for 24h to Trypsin-3 (0.5-10nM) on the baso-lateral side. Paracellular permeability was measured by the passage of dextran FITC (3000kDa, Sigma) from the apical to the basal medium, as previously described[ 17].
  • mice were submitted to intraco Ionic administration of Trypsin-3 (10 U/mouse), followed by colorectal distensions at 0, 1, 3, 6 and 9-hours time points, as previously described[3].
  • mice were intracolonically administered with increasing doses of Trypsin-3 (0.1, 1 or 10 U/mouse), followed by colorectal distension 3 hours later.
  • Mice from the control group were administered intracolonically with vehicle (10% v/v absolute ethanol and 10% v/v Tween- 80)[19]. Similar experiments were repeated in PAR2-deficient mice and wild-type littermates[3].

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Biomedical Technology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention appartient au domaine du traitement des maladies intestinales associées à des troubles de la perméabilité intestinale, telles que le syndrome de l'intestin irritable (SII), les maladies inflammatoires chroniques de l'intestin (MICI), la maladie coeliaque, ou la pouchite. En particulier, l'invention concerne des inhibiteurs de la trypsine-3, destinés à être utilisés dans le traitement du syndrome de l'intestin irritable (SII), y compris l'hypersensibilité au gluten. Les inventeurs ont démontré que les cellules épithéliales intestinales stimulées libéraient une activité de type trypsine spécifiquement depuis leur pôle basolatéral. Cette activité était capable d'activer des neurones sensoriels. Dans les côlons de patients atteints de SII, une augmentation de l'activité de type trypsine était associée à l'épithélium. Les inventeurs ont déterminé que la trypsine-3 était la seule forme de trypsine régulée à la hausse dans les cellules épithéliales intestinales stimulées et dans les tissus de patients atteints de SII. La trypsine-3 était capable de transmettre un signal aux neurones entériques sous-muqueux humains et aux neurones sensoriels murins, et d'induire une hypersensibilité viscérale in vivo, dans les deux cas via un mécanisme dépendant du récepteur-2 activé par une protéase.
PCT/EP2017/083743 2016-12-21 2017-12-20 Méthode de traitement de maladies intestinales telles que le syndrome de l'intestin irritable (sii) WO2018115083A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16306760 2016-12-21
EP16306760.6 2016-12-21

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WO2018115083A1 true WO2018115083A1 (fr) 2018-06-28

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WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
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US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5270163A (en) 1990-06-11 1993-12-14 University Research Corporation Methods for identifying nucleic acid ligands
US5475096A (en) 1990-06-11 1995-12-12 University Research Corporation Nucleic acid ligands
WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
US6506559B1 (en) 1997-12-23 2003-01-14 Carnegie Institute Of Washington Genetic inhibition by double-stranded RNA
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WO2001036646A1 (fr) 1999-11-19 2001-05-25 Cancer Research Ventures Limited Inhibition d"expression genique a l"aide d"arn bicatenaire
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