EP0781333A1 - Therapie genique destinee a la transplantation et a des etats inflammatoires ou thrombotiques - Google Patents

Therapie genique destinee a la transplantation et a des etats inflammatoires ou thrombotiques

Info

Publication number
EP0781333A1
EP0781333A1 EP95931935A EP95931935A EP0781333A1 EP 0781333 A1 EP0781333 A1 EP 0781333A1 EP 95931935 A EP95931935 A EP 95931935A EP 95931935 A EP95931935 A EP 95931935A EP 0781333 A1 EP0781333 A1 EP 0781333A1
Authority
EP
European Patent Office
Prior art keywords
thrombomodulin
cells
dna encoding
tissue
promoter
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Withdrawn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
EP95931935A
Other languages
German (de)
English (en)
Inventor
Fritz H. Bach
Christopher Wrighton
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beth Israel Deaconess Medical Center Inc
Original Assignee
Novartis AG
Beth Israel Deaconess Medical Center Inc
Beth Israel Hospital Association
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novartis AG, Beth Israel Deaconess Medical Center Inc, Beth Israel Hospital Association filed Critical Novartis AG
Publication of EP0781333A1 publication Critical patent/EP0781333A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/7455—Thrombomodulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • 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
    • 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
    • A01K2217/05—Animals comprising random inserted nucleic acids (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
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • 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
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/108—Swine
    • 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
    • A01K2267/02—Animal zootechnically ameliorated
    • A01K2267/025—Animal producing cells or organs for transplantation
    • 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
    • A01K2267/0368—Animal model for inflammation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • C12N2799/00—Uses of viruses
    • C12N2799/02—Uses of viruses as vector
    • C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
    • C12N2799/027—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from a retrovirus

Definitions

  • thrombomodulin In response to injury, inflammation or immunologic challenge, such as occurring in connection with allogeneic or xenogeneic transplantation of tissues or organs, as well as other inflammatory conditions such as various autoimmune diseases or sepsis, the endothelium is changed to a dysfunctional or "activated” pro-coagulatory state.
  • An aspect of this conversion occurring in the presence of cytokines such as tumor necrosis factor (TNF or TNF ⁇ ) is the loss or consumption of thrombomodulin from the endothelial cell surface. This reduction in thrombomodulin has been ascribed to downregulation at the transcriptional level [Yu et al., J. Biol. Che . 2667 (1992) 23237-23247].
  • the donor species may be any suitable species which is the same or different from the recipient species and which is able to provide the appropriate endothelial cells, tissue or organs for transplantation or grafting.
  • human TM protein is expressed from cells of a different mammalian species, which cells have been placed or grafted into a human recipient.
  • pig donors will be suitable, but any other mammalian species, e.g. bovine, may be suitable.
  • porcine endothelial cells, or the progenitor cells thereof can be recruited from porcine subjects, genetically modified, and implanted into either the autologous donor or into another mammalian, e.g. human subject.
  • This type of gene transfer substrate is constructed by conjugating the thrombomodulin gene to a polypeptide ligand for an acceptor on an endothelial cell.
  • An inflammatory stimulus which leads to activation of endothelial cells by serum factors such as TNF occurs in a wide variety of pathological conditions, including injuries, burns, septic shock, autoimmune disease, allogeneic or xenotransplantation transplantation, surgery, etc. Further diseases include those where there is an increase in propensity for thrombus formation (e.g.
  • FIG. 5 shows the Northern blot of RNA (16 h exposure) from PAEC culture cells probed with the EcoRI fragment of pUC.TM.CWl ; untransduced PAEC; EAhy926; NIH 3T3; and NTK-2.TM.CW1 transduced, positive selected NIH3T3.
  • the lanes contain 10 ⁇ g RNA.
  • the inte ⁇ olated size of thrombomodulin mRNA is 3.7 kilobases.
  • RNA species predominate: (1) a 3-3.5 kb sequence, corresponding to the tk driven transcript; and (2) an approximately 5.5 kb sequence hybridizable with a TM probe and a probe for G418 resistance, evidencing transcriptional readthrough, starting with the LTR driven transcription and continuing from the neo gene through the tk and TM sequence, corresponding to a 5'-LTR to 3'LTR transcript.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Hematology (AREA)
  • Biophysics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Procédé de modification génétique de cellules de mammifères afin de rendre celles-ci moins sensibles à un stimulus inflammatoire ou immunologique, notamment pour diminuer la tendance des cellules endothéliales à provoquer une coagulation lorsque celles-ci sont soumises à une activation inflammatoire ou immune, ce procédé consistant à modifier génétiquement les cellules en insérant dans celles-ci l'ADN codant la thrombomoduline aux fins d'expression de la thrombomoduline fonctionnelle à partir de ces cellules, dans des conditions d'activation cellulaire. On peut effectuer ce procédé, soit in vivo soit in vitro (ex vivo), celui-ci étant indiqué dans une transplantation, de même que dans le traitement d'états systémiques ou inflammatoires locaux caractérisés par la thrombose.
EP95931935A 1994-08-26 1995-08-25 Therapie genique destinee a la transplantation et a des etats inflammatoires ou thrombotiques Withdrawn EP0781333A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US29694594A 1994-08-26 1994-08-26
US296945 1994-08-26
PCT/EP1995/003379 WO1996006933A1 (fr) 1994-08-26 1995-08-25 Therapie genique destinee a la transplantation et a des etats inflammatoires ou thrombotiques

Publications (1)

Publication Number Publication Date
EP0781333A1 true EP0781333A1 (fr) 1997-07-02

Family

ID=23144206

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95931935A Withdrawn EP0781333A1 (fr) 1994-08-26 1995-08-25 Therapie genique destinee a la transplantation et a des etats inflammatoires ou thrombotiques

Country Status (5)

Country Link
EP (1) EP0781333A1 (fr)
JP (1) JPH10508187A (fr)
AU (1) AU3518695A (fr)
CA (1) CA2197427A1 (fr)
WO (1) WO1996006933A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980887A (en) * 1996-11-08 1999-11-09 St. Elizabeth's Medical Center Of Boston Methods for enhancing angiogenesis with endothelial progenitor cells
US8075880B2 (en) 1999-01-11 2011-12-13 Steward St. Elizabeth's Medical Center Of Boston, Inc. Compositions and methods for regulating angiogenesis
JP2004503216A (ja) 2000-05-22 2004-02-05 ジョンズ・ホプキンス・ユニバーシティ 疾患を阻止するための血管移植片の遺伝子工学処理
US7501114B2 (en) * 2002-12-02 2009-03-10 Biovec, Llc Ex vivo and in vivo expression of the thrombomodulin gene for the treatment of cardiovascular and peripheral vascular diseases
US9388427B2 (en) 2002-12-02 2016-07-12 Biovec, Llc In vivo and ex vivo gene transfer into renal tissue using gutless adenovirus vectors
US7803365B2 (en) 2002-12-02 2010-09-28 Biovec, Llc Ex vivo and in vivo expression of the thrombomodulin gene for the treatment of cardiovascular and peripheral vascular diseases
US7470538B2 (en) 2002-12-05 2008-12-30 Case Western Reserve University Cell-based therapies for ischemia
CA2515916A1 (fr) * 2003-02-25 2004-09-10 Biovec B.V. Applications therapeutiques du gene de la thrombomoduline au moyen de vecteurs viraux et non viraux
AU2005219472A1 (en) * 2004-03-04 2005-09-15 The University Of British Columbia Thrombomodulin (THBD) haplotypes predict outcome of patients

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04507041A (ja) * 1988-12-13 1992-12-10 アメリカ合衆国 遺伝工学により修飾された内皮細胞およびその利用方法
ATE163046T1 (de) * 1990-10-31 1998-02-15 Somatix Therapy Corp Genetische veränderung von endothelzellen
EP0670737A4 (fr) * 1992-03-26 1996-05-29 Gensia Inc Therapie in vivo recourant a des peptides.
WO1994027612A1 (fr) * 1993-05-20 1994-12-08 Baylor College Of Medicine Therapie genetique contre une maladie cardiovasculaire
US5645829A (en) * 1993-06-18 1997-07-08 Beth Israel Hospital Association Mesothelial cell gene therapy
AU695618B2 (en) * 1994-04-11 1998-08-20 Baylor College Of Medicine Compositions and methods for gene therapy to treat disease

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9606933A1 *

Also Published As

Publication number Publication date
AU3518695A (en) 1996-03-22
CA2197427A1 (fr) 1996-03-07
JPH10508187A (ja) 1998-08-18
WO1996006933A1 (fr) 1996-03-07

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