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WO2003004063A1 - Procede de therapie genique destine au traitement des carcinomes positifs a recepteur du gnrh par l'activation, specifique aux cellules tumorales et induite par le gnrh, d'un gene therapeutique, constructions d'acide nucleique et vecteurs associes - Google Patents

Procede de therapie genique destine au traitement des carcinomes positifs a recepteur du gnrh par l'activation, specifique aux cellules tumorales et induite par le gnrh, d'un gene therapeutique, constructions d'acide nucleique et vecteurs associes Download PDF

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Publication number
WO2003004063A1
WO2003004063A1 PCT/DE2002/002388 DE0202388W WO03004063A1 WO 2003004063 A1 WO2003004063 A1 WO 2003004063A1 DE 0202388 W DE0202388 W DE 0202388W WO 03004063 A1 WO03004063 A1 WO 03004063A1
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WIPO (PCT)
Prior art keywords
gnrh
nucleic acid
acid construct
vector
gene
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PCT/DE2002/002388
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German (de)
English (en)
Inventor
Günter EMONS
Carsten GRÜNDKER
Abdolhamid Huschmand Nia
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Georg-August Universität Göttingen
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Priority claimed from EP02010650A external-priority patent/EP1273309A1/fr
Application filed by Georg-August Universität Göttingen filed Critical Georg-August Universität Göttingen
Priority to DE10292896T priority Critical patent/DE10292896D2/de
Publication of WO2003004063A1 publication Critical patent/WO2003004063A1/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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • 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
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4705—Regulators; Modulating activity stimulating, promoting or activating activity
    • 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
    • C12N15/67—General methods for enhancing the expression
    • 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
    • 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

Definitions

  • the invention relates to nucleic acid constructs and vectors containing them for introduction into gonadotropin-releasing hormone (GnRH) -positive carcinomas and to their use for the treatment of GnRH-positive tumors.
  • GnRH gonadotropin-releasing hormone
  • Endometrial cancer is the most common gynecological cancer in the western world. In most cases, endometrial cancer is diagnosed at an early stage, so surgery or chemotherapy offer a good chance of recovery. Steroid receptor negative tumors in the elderly
  • Ovarian tumors are less common, but have much less favorable prognoses and often lead to death. Although ovarian cancer occurs relatively rarely, it causes more deaths than all other gynecological cancers combined. Effective surgical techniques and chemotherapy procedures are well established, but there is little chance of recovery in advanced stages or relapses.
  • the object of the invention is to provide means for the treatment of the above. To provide tumor types.
  • nucleic acid construct which contains a therapeutic gene, the gene product of which triggers the production of a cytotoxic active substance in a cell, under the control of a nucleus factor kappa .0 B (NFB) -specific promoter.
  • NFB nucleus factor kappa .0 B
  • GnRH gonadotropin releasing hormone
  • GnRH receptor The signal transduction of the GnRH receptor in gynecological tumors differs fundamentally from that in the hypothalamus and pituitary (Gründker et al. 2002). GnRH and its analogues induce only in endometrial and OVA rialkarzinomzellen GnRH receptor mediates a 5- to 8-fold increase in activated "5 tivity of the transcription factor nucleus factor B (NFB).
  • NFB transcription factor nucleus factor B
  • GnRH-induced NFB activation is now used according to the invention to express a tumor cell-specific expression of an introduced effector gene (hereinafter also referred to as a therapeutic gene) under the control of an NFB-dependent promoter.
  • the tumor cells are constructed with a nucleic acid construct which contains the effector gene under the control of the NFB promoter, preferably in a vector, transfected.
  • This gene can then be activated in a target cell-specific manner by activating NFB using GnRH analogs, so that an inactive active substance precursor (pro-drug) is only converted into a cytotoxic active substance in tumor cells carrying GnRH receptor and thus target cell-specific cytotoxic therapy 5 is made possible.
  • This form of therapy can be used for all GnRH receptor-expressing carcinomas.
  • ovarian > 80% of tumors expressing the GnRH receptor
  • breast cancers > 50% of the tumors expressing the GnRH receptor
  • prostate cancers no exact numbers are known yet, what percentage of these tumors
  • o express the GnRH receptor.
  • the therapeutic gene within the construct according to the invention must be able to produce a cytotoxic substance in the target cell, i.e. of a cytotoxic agent in any way.
  • a cytotoxic agent in any way.
  • the gene product of the therapeutic gene is an enzyme which can convert an active substance precursor which is present in or supplied to the cell into the cytotoxic active substance.
  • the therapeutic gene is only activated in GnRH receptor-positive cells, in that an NFB-specific promoter induces the activation of the gene when GnRH or a GnRH analogue is released or delivered.
  • the NFB-specific pro motor preferably contains at least one copy of the kappaB enhancer, in particular 4 to 6 copies, fused to a promoter suitable for activating the therapeutic gene.
  • the principle on which the invention is based is that a therapeutic gene or effector gene is under the control of the NFB promoter, which is specific for tumor cells via GnRH (LHRH) or GnRH analogs in GnRH receptor-positive tumor cells (ovary, endometrial , Breast and prostate tumors) is activated.
  • the individual therapeutic gene is not important, so that the execution of the
  • the therapeutic genes are primarily suicide genes that trigger the death of the target cell, although therapeutic genes that enable real therapy of the target cell (reprogramming of the cancer cell) .5 are not excluded.
  • the therapeutic gene is the herpes simplex virus (HSV) thymidine kinase gene.
  • HSV-TK gene is placed under the control of the HSV-TK promoter. HSV-TK converts non-toxic ganciclovir and its descendants into toxic ganciclovir triphosphate (or its descendants) (advantage: bystander effect).
  • the therapeutic gene is the varicella zoster V / ' ti / s thymidine kinase gene.
  • VZV-TK converts non-toxic 6-methoxypurine arabinonucleoside (araM) into toxic adenine Arabinonucleoside triphosphate (araATP).
  • the therapeutic gene is the Eche chia co // cytosine deaminase gene.
  • E.coli-CD When activated by a suitable 5 promoter, E.coli-CD converts non-toxic 5-fluorocytosine into toxic 5-fluorouracil (advantage: bystander effect).
  • the nucleic acid construct is present in a plasmid.
  • the minimal configuration of the plasmid consists of at least one copy, preferably 4 to 60 copies, of the B enhancer, which is an NFB binding site, fused to a promoter which specifically induces the therapeutic gene. Fusing the KappaB enhancer with the promoter gives an NFB-specific promoter for the therapeutic gene.
  • the construct also contains at least one PolyA sequence.
  • the construct can additionally contain a sequence for the expression of the active substance precursor in the target cells.
  • This generally includes at least one coding sequence for the active substance precursor and a suitable promoter.
  • the construct is introduced into the tumor target cells in a liposomal vector.
  • Kim et al. describe, for example, an efficient liposomal method that can also be used here to transfect human ovarian cancer cells.
  • the nucleic acid construct or the vector according to the invention can be contained, for example, in an injection solution or an infusion solution.
  • This preparation can additionally contain the required active substance precursor or be provided for co-application with it, provided the active substance precursor is not present in the cell or is coded on the nucleic acid construct.
  • the preparation with the nucleic acid construct or the vector which contains this construct is administered in chronological coordination with GnRH or a GnRH analog and optionally the active substance precursor or a plasmid coding for the active substance precursor.
  • the tumor treatment is carried out according to the following scheme:
  • nucleic acid construct a) introducing the nucleic acid construct or the vector according to one of the claims: 5 claims 1 to 9 into tumor target cells; b) administration of GnRH or a GnRH analog at intervals of step a); c) administration of an active substance precursor which is converted into the active substance by the gene product of the therapeutic gene contained in the nucleic acid construct
  • the GnRH or the GnRH analog is given in an advantageous procedure 8 to 48 hours after the construct or the vector has been introduced into the target cells.
  • Triptorelin is very advantageously given as the GnRH analog, preferably systemically.
  • the bare construct or the vector can be introduced by intraperitoneal injection.
  • the treatable tumors are reached so well.
  • GnRH or a GnRH analogue is then preferably administered intraperitoneally or intravenously.
  • the active substance precursor is preferably administered intraperitoneally after or with the GnRH or GnRH analog.
  • the active substance precursor is additionally encoded on the nucleic acid construct.
  • the plasmid “pNFB-TK” is used.
  • the plasmid “pNFB-TK” was constructed to express the effector gene herpes simplex virus thymidine kinase (HSV-TK) by NFB, which is specifically activated via GnRH (LHRH) and its analogs in GnRH (LHRH) receptor positive tumor cells.
  • the plasmid "pNFB-TK” contains 4 tandem copies of the B enhancer fused to the herpes simplex virus thymidine kinase promoter followed by the herpes simplex virus thymidine kinase gene with polyA tail.
  • the plasmid "pNFB-TK” is injected intraperitoneally together with a transfection reagent based on liposomes. After 24 hours, a GnRH (LHRH) analog is injected. The binding of the GnRH (LHRH) analogue to the GnRH (LHRH) receptor of the tumor cell leads to the activation of NFB. Activated NFB binds to the B enhancer of the plasmid "pNFB-TK” and thus induces the expression of the herpes simple virus thymidine kinase gene.
  • GnRH (LHRH) and its analogues cannot activate NFB on normal cells that do not express GnRH (LHRH) receptors.
  • the mechanism of NFB activation by GnRH (LHRH) and its analogues is limited to tumors of reproductive organs.
  • GnRH LHRH
  • GnRH analogs bind to the GnRH receptor on the cell surface of the tumor cell. This activates the tumor-specific nucleus factor kappa B (NFKB). Activated NFKB binds to the ⁇ B binding site of the plasmid and thereby induces the expression of the effector gene (e.g. herpes
  • the gene product is an enzyme (e.g. herpes simplex virus thymidine kinase), which catalyzes the conversion of the active ingredient precursor (e.g. ganciclovir) into an active ingredient (e.g. ganciclovir triphosphate). This leads to the death of the tumor cell.
  • an enzyme e.g. herpes simplex virus thymidine kinase
  • therapeutic gene effector gene (here as an example herpes simple virus thymidine kinase)
  • TK thymidine
  • the two ovarian carcinoma cell lines SK-OV-3 and SW 626 and the endometrial carcinoma cell line MFE 296 reacted negatively.
  • more than 80% of the ovarian and endometrial carcinomas showed high-affinity binding sites (Kd 0.1 - 90 nmol / L) for GNRH. Due to this high frequency of GNRH receptor expression, the GnRH receptor is well suited as a target for target cell-specific therapy.
  • GnRH receptor expression was only found in the reproductive organs ovary, myometrium, endometrium, tube and cervix as well as in the placenta and breast except in the pituitary and hypothalamus (Kakar et al. 1994 and own unpublished data). All non-reproductive organs, including the lymphatic and hematopoietic systems, were GnRH receptor negative.
  • the hypothalamus and pituitary gland are not affected by local therapy via the GNRH receptor (intra-tonal application). Furthermore, NFB becomes positive in pituitary GnRH receptor Cells not activated (see the next two sections). In addition, activated NFB would not be toxic in these non-proliferating cells.
  • the reproductive organs such as the uterus and ovary are removed in the event of carcinomas.
  • the breast tissue like the pituitary and hypothalamus, is not affected. Because the vast majority of endometrial and ovarian carcinomas express GnRH receptors, but only very few normal tissues have GnRH receptors, targeting via GnRH receptor appears to be particularly suitable for target cell-specific therapy.
  • the signal of GnRH receptor activation in the tumor cells is passed on by G-protein i and not by G-protein q.
  • An important mechanism is the interaction of the GnRH receptor with the mitogenic signal transduction mediated by growth factors.
  • MAP kinase assay it could be shown that the MAP kinase activity induced by EGF can be completely suppressed by GnRH analogues.
  • GnRH analogues are able to inhibit the EGF-induced expression of the immediate early response gene c-fos in a dose-dependent manner in all examined ovarian and endometrial carcinoma cell lines with GnRH receptor expression. Nanomolar concentrations are sufficient to push the c-fos expression to a basal level of non-proliferating cells.
  • GnRH controls the growth of the tumor cells through interaction of the GnRH receptor with the mitogenic signal transduction of the growth factors. Activation of the NFB transcription factor by GnRH analogues in ovarian and endometrial cancer cells:
  • NFB can be activated by GnRH. This fact makes the therapeutic concept of activating NFB via the GnRH receptor in order to activate its control to activate a therapeutic gene looks promising.
  • mice 5 Hec-1 B endometrial carcinoma cells were administered intraperitoneally. After the tumor cells had grown, the reporter gene plasmid NFB-LacZ in combination with the transfection reagent Lipofect was administered intraperitoneally to the mice. After 24 hours, the control mice were injected with saline and the experimental mice with the GnRH agonist triptorelin intravenously. Another 24 hours later, the animals were killed, the organs and the tumors removed and then stained with X-Gal. Only tumors from mice treated with triptorelin were stained blue. NFB-LacZ was not activated without triptorelin. The ovary and uterus were colored blue both with and without triptorelin. All other organs (brain, heart, lungs, spleen, liver, kidney, stomach, intestine) were not stained with or without triptorelin.
  • NFB appears to be constitutively active in the ovary and uterus. However, this is negligible, since these organs are removed anyway in ovarian and endometrial cancer. NFB is not activated in all other organs examined, as long as inflammation of these organs is avoided.
  • the reporter gene LacZ could be expressed in the tumor solely by liposomal transfection mediated by NFB. All other organs with the exception of the ovary and uterus showed no expression.
  • Luteinizing hormone-releasing hormone induces nuclear factor B-activation and inhibits apoptosis in ovarian cancer cells. Journal of Clinical Endocrinology and Metabolism 85: 3815-3820
  • IVDU (E) -5- (2-iodovinyl) -2'-deoxyuridine.

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Abstract

L'activation de NFKB induite par le GnRH permet d'exprimer, de manière spécifique aux cellules tumorales et sous contrôle d'un promoteur dépendant de NFKB, un gène introduit. A cet effet, les cellules tumorales sont transfectées par un vecteur contenant le gène effecteur sous contrôle du promoteur de NFKB. Ensuite, ce gène est activé de façon spécifique aux cellules cibles par l'activation de NFKB par des agonistes du GnRH de telle manière que seulement dans les cellules tumorales porteuses du récepteur du GnRH, un pro-principe (prodrogue) inactif soit transformé en un principe actif cytotoxique, ce qui permet une thérapie cytotoxique spécifique aux cellules cibles.
PCT/DE2002/002388 2001-07-05 2002-07-02 Procede de therapie genique destine au traitement des carcinomes positifs a recepteur du gnrh par l'activation, specifique aux cellules tumorales et induite par le gnrh, d'un gene therapeutique, constructions d'acide nucleique et vecteurs associes WO2003004063A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE10292896T DE10292896D2 (de) 2001-07-05 2002-07-02 Gentherapeutisches Verfahren zur Behandlung von GnRH-Rezeptor-positiven Karzinomen durch GnRH induzierte tumorzellspezifische Aktivierung eines therapeutischen Gens, zugehörige Nukleinsäurekonstrukte und Vektoren

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10132607.6 2001-07-05
DE10132607 2001-07-05
EP02010650A EP1273309A1 (fr) 2001-07-05 2002-05-13 Méthode thérapeutique pour le traitement de carcinomes "GnRH-receptor" positifs par activation spécifique des cellules tumorales induite par GnRH d'un gène thérapeutique, acides nucléiques et vecteurs correspondants
EP02010650.6 2002-05-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008113983A3 (fr) * 2007-03-16 2009-01-15 Univ Wolverhampton Molécule amplifiant la transcription
EP2350316A1 (fr) * 2008-10-20 2011-08-03 Pharmatest Services Ltd. Procédés et utilisations mettant en uvre des aberrations génétiques de nav3 et l expression aberrante de gènes multiples

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP0657539A1 (fr) * 1989-08-30 1995-06-14 The Wellcome Foundation Limited Substances nouvelles pour la thérapie du cancer
WO1998042364A1 (fr) * 1997-03-27 1998-10-01 Demegen, Inc. Compositions de peptides lytiques/ligands et leurs procedes d'utilisation
WO1999035280A1 (fr) * 1998-01-06 1999-07-15 Bavarian Nordic Research Institute A/S Reconstitution de vecteur retroviral (vecteur recon) pour l'expression ciblee de genes
WO2001036446A2 (fr) * 1999-11-17 2001-05-25 The University Of Bristol Traitement de maladies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0657539A1 (fr) * 1989-08-30 1995-06-14 The Wellcome Foundation Limited Substances nouvelles pour la thérapie du cancer
WO1998042364A1 (fr) * 1997-03-27 1998-10-01 Demegen, Inc. Compositions de peptides lytiques/ligands et leurs procedes d'utilisation
WO1999035280A1 (fr) * 1998-01-06 1999-07-15 Bavarian Nordic Research Institute A/S Reconstitution de vecteur retroviral (vecteur recon) pour l'expression ciblee de genes
WO2001036446A2 (fr) * 1999-11-17 2001-05-25 The University Of Bristol Traitement de maladies

Non-Patent Citations (3)

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Title
GRUENDKER CARSTEN ET AL: "Luteinizing hormone-releasing hormone induces nuclear factor kappaB-activation and inhibits apoptosis in ovarian cancer cells.", JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 85, no. 10, October 2000 (2000-10-01), pages 3815 - 3820, XP002207797, ISSN: 0021-972X *
HUIRNE J A F ET AL: "Gonadotropin-releasing-hormone-receptor antagonists", LANCET, XX, XX, vol. 358, no. 9295, 24 November 2001 (2001-11-24), pages 1793 - 1803, XP004328378, ISSN: 0140-6736 *
RAHMAN N A ET AL: "Transgenic mouse models for gonadal tumorigenesis.", MOLECULAR AND CELLULAR ENDOCRINOLOGY. IRELAND 25 OCT 1998, vol. 145, no. 1-2, 25 October 1998 (1998-10-25), pages 167 - 174, XP002207798, ISSN: 0303-7207 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008113983A3 (fr) * 2007-03-16 2009-01-15 Univ Wolverhampton Molécule amplifiant la transcription
EP2350316A1 (fr) * 2008-10-20 2011-08-03 Pharmatest Services Ltd. Procédés et utilisations mettant en uvre des aberrations génétiques de nav3 et l expression aberrante de gènes multiples
EP2350316A4 (fr) * 2008-10-20 2012-05-30 Pharmatest Services Ltd Procédés et utilisations mettant en uvre des aberrations génétiques de nav3 et l expression aberrante de gènes multiples

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