EP1185635A2 - Animaux transgeniques non-humains deficients en fonction "gas6" (growth arrest-specific gene 6) et leur utilisation - Google Patents

Animaux transgeniques non-humains deficients en fonction "gas6" (growth arrest-specific gene 6) et leur utilisation

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Publication number
EP1185635A2
EP1185635A2 EP00935193A EP00935193A EP1185635A2 EP 1185635 A2 EP1185635 A2 EP 1185635A2 EP 00935193 A EP00935193 A EP 00935193A EP 00935193 A EP00935193 A EP 00935193A EP 1185635 A2 EP1185635 A2 EP 1185635A2
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EP
European Patent Office
Prior art keywords
gas6
cells
mice
endothelial
receptor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00935193A
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German (de)
English (en)
Inventor
Peter Carmeliet
Désiré COLLEN
Bjorn Dahlback
Pablo Garcia De Frutos
Cristina Aparicio
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Desire Collen Research Foundation vzw
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Desire Collen Research Foundation vzw
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Priority to EP00935193A priority Critical patent/EP1185635A2/fr
Publication of EP1185635A2 publication Critical patent/EP1185635A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A01K67/0276—Knock-out vertebrates
    • 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
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0375—Animal model for cardiovascular diseases

Definitions

  • Non-human transqenic animals deficient in Gas6 function and their use.
  • the present invention relates to the manufacture of a medicament for the treatment of endothelial dysfunction.
  • the present invention further relates to the use of an inhibitor of the Gas6 function and/or an inhibitor of a Gas6 receptor for the manufacture of said medicament.
  • the endothelium is uniquely positioned at the interface between the blood and the vessel. As such, it performs multiple functions: it is involved in the regulation of coagulation, leukocyte adhesion in inflammation, vessel tone, and vascular smooth muscle cell growth, and also acts as a barrier to transvascular flux of liquids and solutes (Griendling & Alexander, 1996). Far from being a passive participant in these events, it is a dynamic tissue, secreting and modifying vasoactive substances, influencing the behaviour of other cell types, and regulating extracellular matrix production and composition.
  • Cardiovascular disorders including atherothrombosis, stroke, arterial (re)-stenosis, ischemic heart disease, myocardial infarction, diabetic macro- and microangiopathy, allograft arteriosclerosis and the like constitute the leading cause of morbidity and mortality in Westernised societies.
  • a common feature of all these disorders is activation of the endothelium, which induces interaction with leukocytes (Ross, 1999).
  • leukocytes adhere to and infiltrate underneath the endothelium during lipid-induced atherosclerosis (Ross, 1999; Libby et al., 1997; Vadas et al., 1997; Boyle et al., 1997).
  • leukocytes During immune-mediated transplant arteriosclerosis or cuff-induced restenosis, leukocytes adhere to the endothelium, subsequently infiltrate in the intima and media, where they activate medial smooth muscle cells to emigrate in the intima, thereby leading to obstructive intimal thickening (Libby et al., 1992).
  • leukocytes During ischemia/reperfusion, leukocytes have been involved in the production of toxic substances, leading to tissue destruction (Murohara et al., 1995; Dinerman & Mehta, 1990; DeGraba, 1998; Hallenbeck, 1997; Cavanagh et al., 1998).
  • insufficient angiogenesis has been related to impaired responsiveness of the endothelium, such as in the elderly or diabetic patients. Infection and resulting sepsis continue to be important causes of morbidity and mortality, in particular in surgical patients. Emerging evidence implicates the endothelium as a central effector in the inflammatory response (Ahmed & Christou, 1996; McGill et al., 1998; Pajkrt & van Deventer, 1996). Through the expression of surface proteins and secretion of soluble mediators, the endothelium controls vascular tone and permeability, regulates coagulation and thrombosis, and directs the passage of leukocytes into areas of inflammation.
  • Metastasis involves adhesion of tumor cells to the endothelium with subsequent extravasation and colonisation in distant tissues. Adhesion of tumor cells is mediated by similar adhesion molecules as used by leukocytes. Endothelial cells in tumors are activated, express more and distinct adhesion molecules, and are often dysfunctional.
  • Gas6 Growth arrested gene 6
  • fibroblasts increased by serum starvation and contact inhibition, and was therefore implicated in reversible growth arrest (Schneider et al., 1988).
  • Gas6 has significant sequence similarity with anticoagulant protein S but lacks anticoagulant activity due to absence of two thrombin cleavage sites. Both molecules are composed of a Gla domain, four EGF-like repeats and a carboxyterminal tandem globular (G)-domains with homology to steroid hormone- binding globulin that are present in molecules involved in cell growth and differentiation (Nakano et al., 1997a).
  • Gas6 binds members of the Axl family of receptor tyrosine kinases including Axl (also called Ark, Ufo), Sky (also called Rse, Tyro3, Dtk, Etk, Bit) and Mer (also called Eyk, Nyk) (Crosier and Crosier, 1997; Nagata et al., 1996; Stitt et al., 1995).
  • Axl also called Ark, Ufo
  • Sky also called Rse, Tyro3, Dtk, Etk, Bit
  • Mer also called Eyk, Nyk
  • the extracellular domain of these receptors posses Ig-like motifs and fibronectin type III modules, found in cell adhesion molecules.
  • a truncated soluble Axl form is proteolytically generated but it remains unknown whether this soluble receptor acts as a competitive inhibitor for Gas6 by sequestering free ligand, is involved in binding Axl directly and originating a signal distinct from Gas6, or in inactivating the receptor on the cell surface (Costa et al., 1996).
  • Gas6 is expressed in lung and intestine (Manfioletti et al., 1993).
  • Sky is predominantly expressed in the brain
  • Mer is expressed in monocytes (from peripheral blood and bone marrow) and in cells derived from epithelial tissues (lung, kidney) and reproductive tissues (ovary, prostate), but not in unstimulated granulocytes.
  • Axl is also expressed in monocytes but not in unstimulated granulocytes or mature B or T lymphocytes.
  • Gas6 and Axl are expressed by vascular endothelial cells (Manfioletti et al., 1993).
  • Gas6 The function of Gas6 remains largely undetermined and controversial. Gas ⁇ has been reported to inhibit homophiiic Axl-mediated aggregation of myeloid cells (Avanzi et al., 1998), but cell-bound Gas6 may mediate aggregation of myeloid cells via interaction with Axl receptor on adjacent cells (McCloskey et al., 1997). Gas6 did not affect adhesion of granulocytes to resting endothelial cells, while it inhibited granulocyte adhesion to TNF-alpha activated endothelial cells, but only at high concentrations (Avanzi et al., 1998).
  • Gas6 is mitogenic for fibroblasts (Goruppi et al., 1996) and Schwann cells (Li et al., 1996) but not for myeloid cells (Avanzi et al., 1997) or endothelial cells (Avanzi et al., 1998).
  • Gas6 also acts as a survival factor for serum-starved fibroblasts (Goruppi et al., 1996) and GnRH neuronal cells (Allen et al., 1999), presumably via activation of PI3-kinase and Akt kinase (Goruppi et al., 1997).
  • Ark signalling protects against apoptosis induced by serum withdrawal or TNF-alpha, but the increased apoptosis of Ark deficient fibroblasts after serum- withdrawal could not be rescued by Gas6 (Bellosta et al., 1997).
  • Gas6 may play a role in clearance of apoptotic cells by forming a bridge between phosphatidylserine on the surface of apoptotic cells and Axl on phagocytotic cells (Nakano et al., 1997b).
  • endothelial cells exhibit a unique plasticity to rapidly proliferate and migrate, or to become activated to express prothrombotic factors or leukocyte adhesion molecules.
  • Such responsiveness is essential to accommodate rapidly changing needs to vascularize ischemic tissues, to provide hemostasis upon vascular trauma, to mediate leukocyte extravasation in inflamed tissues or to provide adequate vasomotor control during abnormal tissue perfusion.
  • the molecular mechanisms that allow quiescent endothelial cells to exhibit such rapid responsiveness remain undetermined.
  • the present invention concerns an animal deficient in Gas6 function.
  • said animal is a transgenic animal in which the Gas6 alleles are inactivated (Gas6 'A ). More preferably, said animal is a Gas6 " ⁇ mouse.
  • the invention relates to the use of said Gas6 deficient animal to study the role of Gas6.
  • Said Gas6 deficient transgenic animals can be used for screening compounds having an effect, positive or negative, on said endothelial dysfunction.
  • the invention provides a method to screen for inhibitors of Gas6 function and/or inhibitors of a Gas6 receptor that result in an inhibition of the endothelial activation.
  • inhibitors of Gas6 function are soluble forms of the Gas6 receptor and/or Gas6 neutralising antibodies.
  • Gas6 inhibitors may be compounds that prevent the binding of Gas6 to its receptor and/or the activation of said receptor.
  • the invention provides the use of an inhibitor of the Gas6 function and/or an inhibitor of a Gas6 receptor for the manufacture of a medicament to treat endothelial dysfunction.
  • Activation of Gas6 receptor depends on the type of receptor and is known to the people skilled in the art.
  • Gas6 tyrosine kinase type receptors it has been extensively described in W09628548 and refers to the step of causing the intracellular domain of the receptor to phosphorylate tyrosine residues in a substrate polypeptide.
  • Inhibitor of Gas6 receptor any compound that prevents the activation of said receptor.
  • Gas6 neutralising antibody any antibody that prevents Gas6 to execute its function.
  • Inhibitor of Gas6 function any compound that prevents Gas6 to execute its function. This inhibition may be due to actions such as chemical modification, denaturation of the tertiary structure, complex formation or proteolysis.
  • Gas6 function binding of Gas6 with a Gas6 receptor. Bind(ing) means any kind of interaction, be it direct (direct interaction of Gas6 with the extracellular domain of said receptor) or indirect (interaction of Gas6 with one or more identical and/or non- identical compounds resulting in a complex of which one or more compounds can interact with the extracellular domain) that results in activation of the Gas6 receptor.
  • the extracellular domain means the domain as it occurs in the natural Gas6 receptors, or a fragment thereof, eventually fused to other amino acid sequences, characterised in that it is still able to bind Gas6.
  • Compound any chemical or biological compound, including simple inorganic or organic molecules, peptides, peptido-mimetics, proteins, antibodies, carbohydrates, nucleic acids or derivatives thereof.
  • Example 1 inhibition of endothelial activation by Gas6 gene-inactivation in mice
  • the Gas6 gene was inactivated in embryonic stem cells via homologous recombination, and Gas6 deficient mice were generated. Surprisingly, these knockout mice developed normally, survived, and were apparently healthy. However, when the Gas6 deficient mice were challenged with inflammatory stimuli, they were found to be protected against endothelial activation.
  • mice Eight to twelve week old WT and Gas6 " ⁇ mice of either sex with a genetic background of 75% C57BI6 and 25%129/Sv, and weighing 20-30 g, were used. Animals were maintained in an open animal facility and experiments were performed according to the guidelines of the institutional animal care committee. Adult mice were intraperitoneally injected with endotoxin (0, 10 and 20 mg/kg) and after 12 h, mice were anesthetized by intraperitoneal injection of 60 mg/kg sodium pentobarbital. Blood was collected in citrate via vena cava puncture with a 24-gauge needle. Following centrifugation at 3000 rpm for 10 min, plasma was collected and stored at -20° C until analysis.
  • Factor VII activity was measured via the Coatest FVII assay, as described by the manufacturer (Chromogenix, Brussels, Belgium).
  • the coagulant activity of the other factors was determined as a clotting time after mixing the murine plasma with human plasma, deficient in the specific factor and addition of thromboplastin (for Fll, FV, FVII, FX) or kaolin (FIX) in the University Hospital (UZ Gasthuisberg, Leuven, Belgium). All procoagulant activities were expressed as a percent of the procoagulant activity in a plasma pool of adult wild type mice.
  • Plasma fibrinogen was determined by a coagulation rate assay (Vermylen et al., 1963).
  • mice In order to obtain mouse capillary endothelial cells, anaesthetized mice were injected s.c. with 500 ⁇ l of ice-cold matrigel containing VEGF (100 ng/ml) and heparin (300 ⁇ g/ml). After 7 days, the pellet containing neovessels was dissected and enzymatically dispersed using 0.1% type II collagenase (Sigma, St Louis, Mo). Mouse endothelial cells were routinely cultured in T75 flasks coated with 0.1% gelatin in M131 medium supplemented with 5% MVGS (ref S005025; Gibco-BRL). For passage, cells were detached by trypsin/EDTA (0.02-0.05%).
  • VEGF 100 ng/ml
  • heparin 300 ⁇ g/ml
  • TNF- ⁇ stimulation endothelial cells were refed with fresh culture medium containing 100 ng/ml TNF- ⁇ (R&D, Abingdon, UK). After 24 hr, the conditioned medium was harvested and analyzed for the following cytokines: IL-1 ⁇ and IL-6 (QuantikineTM M, R&D, Abindon, UK); ELAM, ICAM, VCAM and tissue factor (all from R&D).
  • mice were intraperitoneally injected with endotoxin (20 mg/kg) and after 90 or 180 min, the mice were anesthetized by intraperitoneal injection of 60 mg kg sodium pentobarbital. Blood was collected in citrate by vena cava puncture with a 24-gauge needle. Following centrifugation at 3000 rpm for 10 min, plasma was collected and stored at -20° C until analysis. Cytokines were measured using QuantikineTM M assays for IL-1 ⁇ , IL-6, IL-10 and TNF- ⁇ according to the manufacturer's instructions (all from R&D, Abindon, UK).
  • mouse endothelial cells were cultured in T75 flasks coated with 0.1 % gelatine in RPMI 1640 medium containing 10% foetal calf serum (Life Technologies, Paisley, UK), 100 IU penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, heparin (100 ⁇ g/ml) and endothelial cell growth supplement (30 ⁇ g/ml).
  • Apoptosis was induced by (i) supplementation of TNF- ⁇ (100 ng/ml; R&D), Fas- ligand (100 ng/ml; R&D), or withdrawal from growth factors (0.1 % foetal calf serum).
  • Apoptosis was quantified by measuring cytoplasmic histone-associated DNA fragments (mono- and oligonucleosomes) using a photometric enzyme immunoassay (Cell Detection ELISA, Boehringer Mannheim, Mannheim, Germany).
  • tissue factor the initiator of blood coagulation
  • a mouse model of arterial stenosis based on ligation is used. Previous studies have indicated that following ligation, the endothelium becomes activated, resulting in adhesion of leukocytes to the endothelium, with subsequent infiltration in the intima and media (Kockx et a/., 1993). Due to leukocyte production of growth factors and cytokines, medial smooth muscle cells become activated, proliferate and migrate backwards into the intima, thereby forming a neointima, rich in smooth muscle cells. Wild type and Gas6 " ⁇ mice were subjected to ligation of the right common carotid artery, just proximal to the bifurcation, with silk 4/0.
  • Ischemic brain injury was achieved by permanently ligating and sectioning the middle cerebral artery. Infarct size was morphometrically measured after TTC staining of 1 mm thick brain slices within 24 hrs after ligation as described by Nagai et al. (1999). Ischemic brain injury was significantly reduced in Gas6 ' ⁇ as compared to Gas6 + mice after ligation of the middle cerebral artery (Table 6).
  • Example 4 in vivo role of Gas6 in angiogenesis
  • endothelial cells in the adult are quiescent, and need to become activated when new blood vessels are formed.
  • Angiogenesis inhibitors have attained significant interest for the treatment of cancer, inflammatory disorders and diabetic retinopathy, as endothelial cells that invade tumors are non-tumoral host-derived cells, that would not become resistant to chemotherapy (Folkman, 1998).
  • Ingrowth of capillaries in matrigel was performed as described by Passanti et al. (1992). Briefly, 500 ⁇ l ice-cold matrigel containing heparin (300 ⁇ g/ml) and rVEGFies (100ng/ml) was injected subcutaneaously into the groin. After 7 days, the matrigel pellet with the neovessels was dissected for analysis of neovascularisation: one part was homogenized to determine the hemoglobin content determined using Drabkin's reagent (Sigma, St. Quentin Fallavier, France), whereas the other part was fixed in 1 % paraformaldehyde for histological analysis.
  • Drabkin's reagent Sigma, St. Quentin Fallavier, France
  • Avanzi, G.C. et al. GAS6 inhibits granulocyte adhesion to endothelial cells.
  • Thromb Haemost 78, 60-64 (1997).
  • Golino, P. et al. Inhibition of leucocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury.
  • Thromb Haemost 77, 783-788 (1997).
  • Table 1 Coagulation and hematological parameters after endotoxin injection (20 mg/kg).
  • mice mice
  • mice Plasma concentrations of coagulation factors (expresses in % of normal pool), platelets and leukocytes in mice within 12 h after injection of endotoxin (0-10 and 20 mg/kg).
  • Table 2 Serum cytokine concentration after endotoxin injection (20 mg/kg).
  • mice Data represent mean ⁇ SD (7 mice) of cytokine serum concentrations in mice after injection of endotoxin (20 mg/kg).
  • Data represent mean ⁇ SD (9) of cytokine concentrations (ng/10 cells).

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Abstract

Il a été démontré que les cellules endothéliales déficientes en Gas6 sont résistantes à l'activation par endotoxine et TNF-α in vitro et in vivo et que les leucocytes ne seront pas ou seront moins extravasés dans les souris déficientes en Gas6. La présente invention concerne également la production de médicament pour le traitement de dysfonctionnements de l'endothélium. En outre, la présente invention concerne l'utilisation d'un inhibiteur de fonction Gas6 et/ou d'un inhibiteur d'un récepteur de Gas6 pour la production de ces médicaments.
EP00935193A 1999-06-10 2000-06-08 Animaux transgeniques non-humains deficients en fonction "gas6" (growth arrest-specific gene 6) et leur utilisation Withdrawn EP1185635A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00935193A EP1185635A2 (fr) 1999-06-10 2000-06-08 Animaux transgeniques non-humains deficients en fonction "gas6" (growth arrest-specific gene 6) et leur utilisation

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99201859 1999-06-10
EP99201859 1999-06-10
PCT/EP2000/005318 WO2000076309A2 (fr) 1999-06-10 2000-06-08 Animaux transgeniques non-humains deficients en fonction 'gas6' (growth arrest-specific gene 6) et leur utilisation
EP00935193A EP1185635A2 (fr) 1999-06-10 2000-06-08 Animaux transgeniques non-humains deficients en fonction "gas6" (growth arrest-specific gene 6) et leur utilisation

Publications (1)

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EP1185635A2 true EP1185635A2 (fr) 2002-03-13

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AU (1) AU5077100A (fr)
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Families Citing this family (9)

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Publication number Priority date Publication date Assignee Title
AU2001260214A1 (en) * 2000-04-13 2001-10-30 D. Collen Research Foudation Vzw Use of inhibition of a gas6 function or of a gas6 receptor for preventing and treating a cardiovascular disease
EP1199081A1 (fr) * 2000-10-20 2002-04-24 Vlaams Interuniversitair Instituut voor Biotechnologie Inhibition de la fonction de gas6 (growth arrest-specific gene) ou du récepteur de gas6 pour le traitement des maladies thromboemboliques
GB2374870A (en) * 2001-01-26 2002-10-30 Thromb X Nv Use of genetically modified multicellular animals in the identification of drug target proteins
DE10130657A1 (de) * 2001-06-27 2003-01-16 Axaron Bioscience Ag Neues endothetial exprimiertes Protein und seine Verwendung
EP1382969A1 (fr) * 2002-07-17 2004-01-21 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Diagnostic et traitement de l'invasion des cellules cancéreuses
EP1563094A4 (fr) * 2002-10-29 2007-04-25 Rigel Pharmaceuticals Inc Modulateurs de l'angiogenese et de la tumorigenese
RU2490632C1 (ru) * 2012-05-17 2013-08-20 Государственное Бюджетное Образовательное Учреждение Высшего Профессионального Образования "Красноярский Государственный Медицинский Университет Имени Профессора В.Ф. Войно-Ясенецкого Министерства Здравоохранения И Социального Развития Российской Федерации" Способ моделирования дисфункции эндотелия in vitro
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
CA3057748A1 (fr) 2017-04-20 2018-10-25 Adc Therapeutics Sa Polytherapie avec un conjugue anticorps anti-axl-medicament

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JPH1179A (ja) * 1997-06-09 1999-01-06 Shionogi & Co Ltd Ｇａｓ６遺伝子改変マウス

Non-Patent Citations (1)

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Title
See references of WO0076309A2 *

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AU5077100A (en) 2001-01-02
WO2000076309A2 (fr) 2000-12-21

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