WO2007044413A2 - Wwox gene, vectors containing the same, and uses in treatment of cancer - Google Patents

Wwox gene, vectors containing the same, and uses in treatment of cancer Download PDF

Info

Publication number
WO2007044413A2
WO2007044413A2 PCT/US2006/038824 US2006038824W WO2007044413A2 WO 2007044413 A2 WO2007044413 A2 WO 2007044413A2 US 2006038824 W US2006038824 W US 2006038824W WO 2007044413 A2 WO2007044413 A2 WO 2007044413A2
Authority
WO
WIPO (PCT)
Prior art keywords
wwox
cancer
cell
cells
expression
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.)
Ceased
Application number
PCT/US2006/038824
Other languages
English (en)
French (fr)
Other versions
WO2007044413A3 (en
Inventor
Carlo M. Croce
Muller Fabbri
Francesco Trapasso
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.)
Ohio State University Research Foundation
Original Assignee
Ohio State University Research Foundation
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 Ohio State University Research Foundation filed Critical Ohio State University Research Foundation
Priority to JP2008534659A priority Critical patent/JP2009511482A/ja
Priority to US12/083,067 priority patent/US20090270484A1/en
Priority to EP06825457A priority patent/EP1940456A4/en
Priority to AU2006302496A priority patent/AU2006302496A1/en
Priority to CA002624531A priority patent/CA2624531A1/en
Publication of WO2007044413A2 publication Critical patent/WO2007044413A2/en
Publication of WO2007044413A3 publication Critical patent/WO2007044413A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • 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
    • 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
    • A61K48/0075—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 delivery route, e.g. oral, subcutaneous
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the invention generally relates to compositions and methods for controlling abnormal cell growth, including but not limited to, that found in cancer, and in particular, lung cancer.
  • Lung cancer is the leading cause of cancer mortality in the United States
  • Nonsmall cell lung cancer accounts for about 80% of lung cancers. Surgery remains the main therapy for NSCLC, but a large fraction of patients cannot undergo curative resection. Despite new drugs and therapeutic regimens, the prognosis for lung cancer patients has not significantly changed in the last 10 years.
  • Recombinant virus gene therapy has been investigated in lung cancer patients; adenovirus (Ad) and retrovirus encoding wild-type p53 have been injected intratumorally in lung cancer clinical trials (2-6).
  • Recombinant Ad injection in lung cancer phase I studies (T) has demonstrated safety and feasibility, and phase I/II clinical trials are currently recruiting patients to evaluate toxicity and efficacy of gene therapy with recombinant Ads.
  • WWOX fragment histidine triad gene (8) at fragile site FRA3B (9). Fragile regions are particularly susceptible to damage on exposure to environmental carcinogens, which are etiological factors in lung cancer. Recently, Yendamuri et al. (H)) have demonstrated that the WWOX(WW domain containing oxidoreductase) gene is also altered in a fraction of nonsmall cell lung cancers. WWOX is located at fragile site FRA 16D (Ii) and encodes a 414-aa protein with two WW domains and a short-chain dehydrogenase domain. WW domains are protein-protein interaction domains, and Wwox interactors with important signaling roles in normal epithelial cells have been identified.
  • Wwox interacts with ⁇ 73 and can trigger redistribution of nuclear p73 to the cytoplasm, suppressing its transcriptional activity (12). Wwox also interacts with Ap2-T transcription factors with roles in cell proliferation (IT). Most recently, Wwox has been reported to compete with Yap protein for binding to the intracellular ErbB4 domain, a transcriptional activator (14). Thus, the Wwox pathway includes a number of downstream signaling proteins that may also serve as cancer therapeutic targets. [0005] The WWOX gene is altered in many types of cancer, including breast, ovary, prostate, bladder, esophagus, and pancreas (15 . -19).
  • the invention provides methods for treating cancer in a subject, comprising administering to the subject a polynucleotide encoding a functional WWOX gene product.
  • the cancer is chosen from lung cancer, breast cancer, ovarian cancer, prostate cancer, bladder cancer, esophageal cancer, and pancreatic cancer.
  • the administration comprises gene therapy, and in some embodiments, recombinant viral gene therapy, such as recombinant adenoviral gene therapy.
  • the invention further provides methods of treating cancer in a subject comprising inducing Wwox expression in at least one cancer cell of the subject.
  • the invention also provides methods of inducing cell growth inhibition in a cancer cell line comprising inducing expression of Wwox in the cell line.
  • the cancer cell or cancer cell line is lung cancer.
  • the invention also provides polynucleotides comprising: a polynucleotide encoding a functional WWOX gene product; and a heterologous promoter operatively linked to the polynucleotide encoding the functional WWOX gene product.
  • the two ends of the polynucleotide are linked, resulting in a circular polynucleotide.
  • the invention also provides vectors comprising a WWOX gene product expression cassette comprising: a polynucleotide encoding a functional WWOX gene product; and a heterologous promoter operatively linked to the polynucleotide encoding the functional WWOX gene product.
  • the vector is a viral vector, and in some embodiments, the viral vector is a recombinant adenoviral vector.
  • the invention also provides cells comprising the viral vector according to the invention.
  • the cells may be lung cells, and in particular, lung cancer cells.
  • the invention also provides pharmaceutical compositions for treating cancer in a subject, comprising: a viral vector, said vector comprising a WWOX gene product expression cassette, said cassette comprising a polynucleotide encoding a functional WWOX gene product and a heterologous promoter operatively linked to the polynucleotide encoding said functional WWOX gene product; and a pharmaceutically acceptable excipient.
  • the viral vector may be, for example, a recombinant adenoviral vector.
  • the composition is formulated for inhalation.
  • the invention still further provides a plasmid, comprising: a polynucleotide encoding a functional WWOX gene product; and a heterologous promoter operatively linked to the polynucleotide encoding said functional WWOX gene product.
  • the invention also provides cells comprising the plasmid according to the invention.
  • the invention also includes methods of treating cancer in a subject, comprising administering to the subject a therapeutic compound capable of reactivating a WWOX gene.
  • the subject is a human.
  • the reactivation of the WWOX gene results in induction of apoptosis.
  • Fig. 1 Expression of Wwox protein.
  • Wwox is detected in U2020 and MCF7 cells but not in H1299, H460, or A549 cells (50 ⁇ g of proteins loaded). Lane 1, H1299; lane 2, H460; lane 3, A549; lane 4, U2020; lane 5, MCF-7. (B) Expression of Wwox after infection with Ad-WWOX (25 ⁇ g loaded).
  • Lane 1 H1299, Ad-WWOX-infected; lane 2, H1299, Ad-GFP-infected; lane 3, H1299; lane 4, H460, Ad-WWOX-infected; lane 5, H460, Ad-GFP-infected; lane 6, H460; lane 7, A549, Ad-WWOX-infected; lane 8, A549, Ad-GFP-infected; lane 9, A549.
  • FIG. 2 Flow cytometry analysis of untreated, Ad-GFP-, and Ad-
  • WWOX-infected cells Wwox-negative A549, H460, and H1299 cells undergo apoptosis 5 days after restoration of Wwox expression by Ad-WWOX infection, but U2020 cells are unaffected. Ad-GFP infection did not induce apoptosis.
  • A Growth of uninfected, Wwox-negative A549, H460, and Hl 299 cells, and cells after infection with Ad-GFP and Ad-WWOX.
  • B Immunoblot detection of PARP and caspase 3.
  • Fig. 4 Inducible expression of Wwox in H1299/I cells.
  • A Cells were cultured in the presence (+) or absence (-) of 10 ⁇ M ponA for 48 hr and tested for Wwox expression. Clones 7 and 2, which expressed the transgene only upon induction with ponA, were used in subsequent experiments. GAPDH expression served as loading control.
  • Fig. 5 Effect of Wwox expression on tumorigenicity of lung cancer cells.
  • A Tumor volume of untreated, Ad-GFP-, and Ad-WWOX-infected A549, H460, and U2020 lung cancer cells. Restoration of Wwox expression in A549 and H460 cells suppressed tumor growth significantly (P ⁇ 0.001) compared with Ad-GFP infected cells.
  • B Tumor volume of untreated, Ad-GFP-, and Ad-WWOX-infected H1299 cells and H1299/r and H1299/I + cells. Tumors were suppressed in Ad- WWOX-infected H1299 cells and in H1299/I + cells.
  • Q Examples of tumor formation by uninfected, Ad-GFP-, and Ad-WWOX-infected A549, H1299/T, and H1299/I + cells.
  • Fig. 6 Ex vivo analysis of H1299/T and H1299/I + cells.
  • A Protein lysates from H 1299 (lane 1), uninduced H 1299/1 " (lanes 2, 3, and 4), and induced H 1299/I + (lane 5) tumors tested for Wwox expression by immunoblot analysis. Wwox was not expressed in the H1299/F or H1299/I + tumors.
  • B A portion of the H1299I ⁇ tumor was plated and cultured, and cells were treated with ponA. Wwox was reexpressed after 48 hr of treatment with 10 ⁇ M ponA, indicating the presence of the inducible WWOX plasmid.
  • Fig. 7 Table 1 - Tumor weight (in grams) ⁇ SD in nude mice.
  • WWOXcDNA from normal human liver RNA was reverse-transcribed by Superscript First-Strand Synthesis (Invitrogen).
  • Double-stranded cDNA was prepared by PCR amplification using the following conditions: 95°C for 3 min, 30 cycles at 94°C for 30 sec, 65°C for 60 sec, 72°C for 30 sec, and 72°C for 7 min; WWOX forward S'-GCCAGGTGCCTCCACAGTCAGCC-S' and JWOJf reverse 5'- TGTGTGTGCCC ATCCGCTCTGAGCTCC AC-3' primers were used.
  • the cDNA was cloned into Adenovator-CMV5(CuO)-IRES-Gi ?
  • P transfer vector (Qbiogene) (11). This vector allows transgene expression driven by the cumate-inducible CMV5(CuO) promoter. An internal ribosome entry site sequence ensures coexpression of GFP.
  • the recombinant plasmid, Ad-WWOX was transfected into modified human fetal kidney HEK-293 CymR cells (Qbiogene) constitutively expressing the CymR protein, which represses the CMV5(CuO) promoter and expression of Wwox during packaging and expansion of the WWOX A ⁇ . After 14-21 days, homologous recombination occurred in cells, leading to plaque formation.
  • Plaques were isolated, and viruses were amplified in HEK-293 CymR cells and purified by CsCl gradient centrifugation. Titers were determined by absorbance measurement (number of viral particles per ml) and plaque assay (plaque-forming units/ml), and transgene expression was assessed by immunoblot using Wwox monoclonal antibody (21). Cells were transduced with recombinant Ads at increasing multiplicities of infection (mois) (number of viral particles per cell), and transduction efficiency was determined by visualization of GFP-expressing cells.
  • mois multiplicities of infection
  • H1299/I clones were selected and tested for inducible WWOX expression after ponA (5-10 ⁇ M) treatment.
  • ponA 5-10 ⁇ M
  • Western Blot Analysis Protein extraction and immunoblot analysis were performed as described in ref. 13. The following primary antisera were used: mouse monoclonal anti-Wwox, 1:500; rabbit polyclonal anti-caspase 3, 1 :1,000 (Cell Signaling Technology, Beverly, MA); rabbit polyclonal anti-caspase 9, 1 :200 (Santa Cruz Biotechnology); mouse monoclonal anti-caspase 8 (Cell Signaling Technology), 1:1,000; rabbit polyclonal anti-PARP [poly(ADP-ribose) polymerase], 1:1,000 (Cell Signaling Technology); and rabbit polyclonal anti- ⁇ -actin, 1:1,000 (Cell Signaling Technology).
  • Cell Growth and Cell Cycle Kinetics Cells (2 x 10 5 ) were infected at mois of 10, 25, 50, 75, and 100 and, at 24 hr intervals, were harvested, stained with trypan blue, and counted (ViCeIl counter, Beckman Coulter). For flow cytometry, cells were harvested 5 days after infection, fixed in cold methanol, RNase-treated, and stained with propidium iodide (50 ⁇ g/ml). Cells were analyzed for DNA content by EPICS-XL scan (Beckman Coulter) by using doublet discrimination gating. All analyses were performed in duplicate.
  • H1299 cells were infected in vitro with Ad-GFP or Ad-WWOX at a moi of 100.
  • H1299/I cells were treated with 10 ⁇ MponA (H1299/I + cells) to induce Wwox expression.
  • H1299/I + injected mice were evaluated for Wwox expression by immunoblot analysis. Fragments from H 1299/I + tumors were cultured and treated with 10 ⁇ M ponA for 2 days to detect expression of inducible Wwox by immunoblot.
  • Statistical Analysis Results of in vitro and in vivo experiments were expressed as mean ⁇ SD. Student's two-sided t test was used to compare values of test and control samples. P ⁇ 0.05 indicated significant difference.
  • Wwox overexpression were assessed after infection at several mois, with Ad-WWOX or Ad-GFP.
  • a sub-Gi population was observed after Ad- WWOX infection in A549, H460, and H 1299 cells that do not express endogenous Wwox but not in endogenous Wwox-positive U2020 cells.
  • Ad-GFP infection did not modify cell cycle profiles.
  • Wwox induction of cell death was moi- and time-dependent (data not shown).
  • H 1299, and U2020 lung cancer cell lines were infected with increasing mois, and the fraction of transduced cells was monitored by confocal microscopy and cell cycle kinetics analyses. Significant differences were observed in cell growth for Ad-WWOX and Ad-GFP infection, at a range of mois, in lung cancer cell lines (A549, H460, and H1299) lacking endogenous Wwox (Fig. 3A). U2020 cells were unaffected by exogenous Wwox expression.
  • H1299/I clone 7 expressed the WWOX transgene only on induction withponA (Fig. AA) and was used in subsequent experiments. Wwox expression increased in a dose-dependent manner after ponA treatment (Fig. AB) from 24 to 72 hr (Tig. 4O.
  • Clone 7 H1299/T (uninduced) cells were plated, and, 24 hr later (day 1),
  • Nude mice were inoculated with 5 x 10 6 A549, H460, and U2020 cells infected in vitro at a moi of 100 with Ad-GFP or Ad-WWOX and cultured for 24 hr. Uninfected cells served as tumorigenic controls. At 28 days after injection, tumor growth was completely suppressed in mice inoculated with Ad-WWOX-mfected H460 cells (Fig. 5A). The average tumor weights for controls (Ad-GFP and untreated H460 cells) at day 28 were 0.61 ⁇ 0.15 g and 0.64 ⁇ 0.11 g, respectively.
  • mice inoculated with Ad-WWOX-mfected A549 cells showed no tumors, and average tumor weight was 0.08 ⁇ 0.03 g, significantly lower (P ⁇ 0.001) than tumors of Adr GF/Mnfected A549 (0.81 ⁇ 0.16 g) and mock-infected A549 (0.86 ⁇ 0.15 g) cells (Table 1).
  • mice injected with infected U2020 cells no tumor growth suppression was observed (Fig. 5A).
  • Wwox expression delivered by viral infection (Ad- WWOX) or by induction of expression of an inactive "endogenous" WWOX gene (H 1299/I + ), was effective in suppressing lung cancer cell growth in nude mice.
  • Ad- WWOX Ad- WWOX
  • H 1299/I + an inactive "endogenous" WWOX gene
  • the ponA-inducible expression of Wwox can be considered a model for the effects of WWOX reactivation after silencing by epigenetic mechanisms.
  • the extent of loss of tumorigenicity after restoring inducible Wwox expression was comparable to the tumor suppression observed after Ad- WWOX expression, both in vitro and in vivo, suggesting that massive overexpression of Wwox is not necessary to effect tumor suppression. This finding suggests that drugs capable of reactivating the epigenetically silenced WWOX gene could be effective in treatment of lung cancer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
PCT/US2006/038824 2005-10-05 2006-10-04 Wwox gene, vectors containing the same, and uses in treatment of cancer Ceased WO2007044413A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2008534659A JP2009511482A (ja) 2005-10-05 2006-10-04 Ｗｗｏｘ遺伝子、同じものを含むベクター、および癌の治療における使用
US12/083,067 US20090270484A1 (en) 2005-10-05 2006-10-04 WWOX Vectors and Uses in Treatment of Cancer
EP06825457A EP1940456A4 (en) 2005-10-05 2006-10-04 WWOX GENE, VECTORS COMPRISING THE SAME, AND USES THEREOF IN THE TREATMENT OF CANCER
AU2006302496A AU2006302496A1 (en) 2005-10-05 2006-10-04 WWOX gene, vectors containing the same, and uses in treatment of cancer
CA002624531A CA2624531A1 (en) 2005-10-05 2006-10-04 Wwox gene, vectors containing the same, and uses in treatment of cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US72375205P 2005-10-05 2005-10-05
US60/723,752 2005-10-05

Publications (2)

Publication Number Publication Date
WO2007044413A2 true WO2007044413A2 (en) 2007-04-19
WO2007044413A3 WO2007044413A3 (en) 2007-11-08

Family

ID=37943348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/038824 Ceased WO2007044413A2 (en) 2005-10-05 2006-10-04 Wwox gene, vectors containing the same, and uses in treatment of cancer

Country Status (7)

Country Link
US (1) US20090270484A1 (enExample)
EP (1) EP1940456A4 (enExample)
JP (1) JP2009511482A (enExample)
CN (1) CN101312740A (enExample)
AU (1) AU2006302496A1 (enExample)
CA (1) CA2624531A1 (enExample)
WO (1) WO2007044413A2 (enExample)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8349560B2 (en) 2007-06-15 2013-01-08 The Ohio State University Research Method for diagnosing acute lymphomic leukemia (ALL) using miR-222
US8664192B2 (en) 2011-03-07 2014-03-04 The Ohio State University Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer
US8859202B2 (en) 2012-01-20 2014-10-14 The Ohio State University Breast cancer biomarker signatures for invasiveness and prognosis
US8916533B2 (en) 2009-11-23 2014-12-23 The Ohio State University Materials and methods useful for affecting tumor cell growth, migration and invasion
US8946187B2 (en) 2010-11-12 2015-02-03 The Ohio State University Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer
US9085804B2 (en) 2007-08-03 2015-07-21 The Ohio State University Research Foundation Ultraconserved regions encoding ncRNAs
US9249468B2 (en) 2011-10-14 2016-02-02 The Ohio State University Methods and materials related to ovarian cancer
US9481885B2 (en) 2011-12-13 2016-11-01 Ohio State Innovation Foundation Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis
US10758619B2 (en) 2010-11-15 2020-09-01 The Ohio State University Controlled release mucoadhesive systems

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105902559A (zh) 2005-08-01 2016-08-31 俄亥俄州立大学研究基金会 用于乳腺癌的诊断、预后和治疗的基于MicroRNA的方法和组合物
WO2007033023A2 (en) 2005-09-12 2007-03-22 The Ohio State University Research Foundation Compositions and methods for the diagnosis and therapy of bcl2-associated cancers
EP2487254B1 (en) 2006-01-05 2015-07-29 The Ohio State University Research Foundation MicroRNA-based methods and compositions for the diagnosis and treatment of solid cancers
EP2514434B1 (en) 2006-01-05 2015-10-21 The Ohio State University Research Foundation MicroRNA-based methods for the diagnosis, prognosis and treatment of lung cancer
JP5490413B2 (ja) 2006-01-05 2014-05-14 ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション 膵内分泌腫瘍及び膵腺房腫瘍におけるマイクロｒｎａ発現異常
ES2446362T3 (es) 2006-03-20 2014-03-07 The Ohio State University Research Foundation Huellas de microARN durante megacariocipoyesis humana
EP2436787B1 (en) 2006-07-13 2016-01-20 The Ohio State University Research Foundation MIR-21 for diagnosing poor survival prognosis colon adenocarcinoma.
JP5426383B2 (ja) 2006-09-19 2014-02-26 ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション 慢性リンパ球性白血病におけるｍｉＲ−２９およびｍｉＲ−１８１によって制御されるＴＣＬ１発現
CA2667617A1 (en) 2006-11-01 2008-05-08 The Ohio State University Research Foundation Microrna expression signature for predicting survival and metastases in hepatocellular carcinoma
CN101627134B (zh) 2007-01-31 2013-11-06 俄亥俄州立大学研究基金会 用于急性髓细胞白血病（aml）的诊断、预后和治疗的基于微rna的方法和组合物
JP5690588B2 (ja) 2007-06-08 2015-03-25 アメリカ合衆国 肝細胞癌のサブタイプを決定し、肝癌幹細胞を検出するための方法
JP2010535782A (ja) 2007-07-31 2010-11-25 ズィ、オハイオウ、ステイト、ユーニヴァーサティ、リサーチ、ファウンデイシャン Ｄｎｍｔ３ａ及びｄｎｍｔ３ｂを標的にすることによるメチル化を元に戻す方法
JP5770472B2 (ja) 2007-08-22 2015-08-26 ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイションＴｈｅ Ｏｈｉｏ Ｓｔａｔｅ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ｆｏｕｎｄａｔｉｏｎ ヒト急性白血病におけるｅｐｈａ７及びｅｒｋリン酸化の調節解除を誘発するための方法及び組成物
CN102137927B (zh) 2007-10-26 2014-03-12 俄亥俄州立大学研究基金会 鉴定脆性组氨酸三联体(Fhit)相互作用的方法及其用途
AU2009257410B2 (en) 2008-06-11 2014-03-06 Fudan University Use of miR-26 family as a predictive marker of hepatocellular carcinoma and responsiveness to therapy
CN110257465A (zh) * 2018-03-12 2019-09-20 中国科学院上海生命科学研究院 Wwox作为防治癌症的药物靶点的应用
US20230293726A1 (en) * 2020-08-11 2023-09-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Method for the treatment of wwox associated diseases
CN115198013A (zh) * 2021-04-14 2022-10-18 迪瑞药业(成都)有限公司 用以鉴别出适用精氨酸剥夺疗法的患者的方法与试剂盒

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044466A1 (en) 1999-12-16 2001-06-21 Women's And Children's Hospital Oxidoreductase gene associated with the fra16d fragile site

Family Cites Families (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4196265A (en) * 1977-06-15 1980-04-01 The Wistar Institute Method of producing antibodies
US4608337A (en) * 1980-11-07 1986-08-26 The Wistar Institute Human hybridomas and the production of human monoclonal antibodies by human hybridomas
US5015568A (en) * 1986-07-09 1991-05-14 The Wistar Institute Diagnostic methods for detecting lymphomas in humans
US5202429A (en) * 1986-07-09 1993-04-13 The Wistar Institute DNA molecules having human BCL-2 gene sequences
US5198338A (en) * 1989-05-31 1993-03-30 Temple University Molecular probing for human t-cell leukemia and lymphoma
WO1993012136A1 (en) * 1991-12-11 1993-06-24 Thomas Jefferson University Detection and treatment of acute leukemias resulting from chromosome abnormalities in the all-1 region
US5633135A (en) * 1991-12-11 1997-05-27 Thomas Jefferson University Chimeric nucleic acids and proteins resulting from ALL-1 region chromosome abnormalities
US6040140A (en) * 1991-12-11 2000-03-21 Thomas Jefferson University Methods for screening and treating leukemias resulting from all-1 region chromosome abnormalities
ES2191018T3 (es) * 1992-10-29 2003-09-01 Univ Jefferson Procedimiento para detectar micrometastasis de cancer de prostata.
US5674682A (en) * 1992-10-29 1997-10-07 Thomas Jefferson University Nucleic acid primers for detecting micrometastasis of prostate cancer
US5985598A (en) * 1994-10-27 1999-11-16 Thomas Jefferson University TCL-1 gene and protein and related methods and compositions
US7175995B1 (en) * 1994-10-27 2007-02-13 Thomas Jefferson University TCL-1 protein and related methods
US6242212B1 (en) * 1996-02-09 2001-06-05 Thomas Jefferson University Fragile histidine triad (FHIT) nucleic acids and methods of producing FHIT proteins
US5928884A (en) * 1996-02-09 1999-07-27 Croce; Carlo M. FHIT proteins and nucleic acids and methods based thereon
AU6951098A (en) * 1997-04-04 1998-10-30 The Texas A & M University System Noninvasive detection of colonic biomarkers using fecal messenger rna
WO2000003685A2 (en) * 1998-07-20 2000-01-27 Thomas Jefferson University Nitrilase homologs
WO2000005419A1 (en) * 1998-07-24 2000-02-03 Yeda Research And Development Company Ltd. Prevention of metastasis with 5-aza-2'-deoxycytidine
US7141417B1 (en) * 1999-02-25 2006-11-28 Thomas Jefferson University Compositions, kits, and methods relating to the human FEZ1 gene, a novel tumor suppressor gene
JP2004516002A (ja) * 2000-04-11 2004-06-03 トーマス・ジェファーソン・ユニバーシティー Ｆｈｉｔ欠損マウスにおけるミュア−トール様症候群
US20020086331A1 (en) * 2000-05-16 2002-07-04 Carlo Croce Crystal structure of worm NitFhit reveals that a Nit tetramer binds two Fhit dimers
US7060811B2 (en) * 2000-10-13 2006-06-13 Board Of Regents, The University Of Texas System WWOX: a tumor suppressor gene mutated in multiple cancers
US20040033502A1 (en) * 2001-03-28 2004-02-19 Amanda Williams Gene expression profiles in esophageal tissue
US20050176025A1 (en) * 2001-05-18 2005-08-11 Sirna Therapeutics, Inc. RNA interference mediated inhibition of B-cell CLL/Lymphoma-2 (BCL-2) gene expression using short interfering nucleic acid (siNA)
EP2390328A1 (en) * 2001-09-28 2011-11-30 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. MicroRNA molecules
US7371736B2 (en) * 2001-11-07 2008-05-13 The Board Of Trustees Of The University Of Arkansas Gene expression profiling based identification of DKK1 as a potential therapeutic targets for controlling bone loss
GB0128898D0 (en) * 2001-12-03 2002-01-23 Biotech Res Ventures Pte Ltd Materials and methods relating to the stabilization and activation of a tumour suppressor protein
EP1496928A4 (en) * 2002-04-08 2005-08-10 Ciphergen Biosystems Inc SERUM BIOMARKERS IN HEPATOCELLULAR CARCINOMA
CA2484920A1 (en) * 2002-04-29 2003-11-13 Thomas Jefferson University Human chronic lymphocytic leukemia modeled in mouse by targeted tcl1 expression
WO2003102215A2 (en) * 2002-05-31 2003-12-11 The Board Of Trustees Of The Leland Stanford Junior University Methods of identifying and isolating stem cells and cancer stem cells
CA2501602A1 (en) * 2002-10-11 2004-04-22 Thomas Jefferson University Novel tumor suppressor gene and compositions and methods for making and using the same
EP1567007B1 (en) * 2002-11-13 2012-02-22 Thomas Jefferson University Compositions and methods for cancer diagnosis and therapy
WO2006031210A1 (en) * 2003-05-29 2006-03-23 Board Of Regents, The University Of Texas Systems Jabi as a prognostic marker and a therapeutic target for human cancer
US20050037362A1 (en) * 2003-08-11 2005-02-17 Eppendorf Array Technologies, S.A. Detection and quantification of siRNA on microarrays
AU2004276823A1 (en) * 2003-09-22 2005-04-07 Merck And Co., Inc Synthetic lethal screen using RNA interference
CN1890382A (zh) * 2003-09-24 2007-01-03 肿瘤疗法科学股份有限公司 检测、诊断和治疗肝细胞癌(hcc)的方法
US20050186589A1 (en) * 2003-11-07 2005-08-25 University Of Massachusetts Interspersed repetitive element RNAs as substrates, inhibitors and delivery vehicles for RNAi
WO2005078139A2 (en) * 2004-02-09 2005-08-25 Thomas Jefferson University DIAGNOSIS AND TREATMENT OF CANCERS WITH MicroRNA LOCATED IN OR NEAR CANCER-ASSOCIATED CHROMOSOMAL FEATURES
IL179285A (en) * 2004-05-14 2011-04-28 Rosetta Genomics Ltd Micrornas and uses thereof
EP2474616B1 (en) * 2004-05-28 2015-07-08 Asuragen, Inc. Methods and compositions involving microRNA
US7635563B2 (en) * 2004-06-30 2009-12-22 Massachusetts Institute Of Technology High throughput methods relating to microRNA expression analysis
US20060037088A1 (en) * 2004-08-13 2006-02-16 Shulin Li Gene expression levels as predictors of chemoradiation response of cancer
US7642348B2 (en) * 2004-10-04 2010-01-05 Rosetta Genomics Ltd Prostate cancer-related nucleic acids
FR2877350B1 (fr) * 2004-11-03 2010-08-27 Centre Nat Rech Scient IDENTIFICATION ET UTILISATION DE miRNAs IMPLIQUES DANS LA DIFFERENCIATION DE CELLULES ISSUES D'UNE LEUCEMIE MYELOIDE
EP1838852A2 (en) * 2004-11-12 2007-10-03 Asuragen, Inc. Methods and compositions involving mirna and mirna inhibitor molecules
CA2590768A1 (en) * 2004-12-14 2006-06-22 Alnylam Pharmaceuticals, Inc. Rnai modulation of mll-af4 and uses thereof
US20070099196A1 (en) * 2004-12-29 2007-05-03 Sakari Kauppinen Novel oligonucleotide compositions and probe sequences useful for detection and analysis of micrornas and their target mRNAs
JP2008528003A (ja) * 2005-01-25 2008-07-31 ロゼッタ インファーマティックス エルエルシー 小ｒｎａ分子の定量方法
US20070065840A1 (en) * 2005-03-23 2007-03-22 Irena Naguibneva Novel oligonucleotide compositions and probe sequences useful for detection and analysis of microRNAS and their target mRNAS
US20070065844A1 (en) * 2005-06-08 2007-03-22 Massachusetts Institute Of Technology Solution-based methods for RNA expression profiling
EP1919512B1 (en) * 2005-08-10 2014-11-12 Alnylam Pharmaceuticals Inc. Chemically modified oligonucleotides for use in modulating micro rna and uses thereof
WO2007033023A2 (en) * 2005-09-12 2007-03-22 The Ohio State University Research Foundation Compositions and methods for the diagnosis and therapy of bcl2-associated cancers
US7390792B2 (en) * 2005-12-15 2008-06-24 Board Of Regents, The University Of Texas System MicroRNA1 therapies
JP5490413B2 (ja) * 2006-01-05 2014-05-14 ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション 膵内分泌腫瘍及び膵腺房腫瘍におけるマイクロｒｎａ発現異常
US7667090B2 (en) * 2006-04-24 2010-02-23 The Ohio State University Research Foundation Transgenic mouse model of B cell malignancy
US20090131348A1 (en) * 2006-09-19 2009-05-21 Emmanuel Labourier Micrornas differentially expressed in pancreatic diseases and uses thereof
CA2663878A1 (en) * 2006-09-19 2008-03-27 Asuragen, Inc. Mir-200 regulated genes and pathways as targets for therapeutic intervention
JP5426383B2 (ja) * 2006-09-19 2014-02-26 ジ・オハイオ・ステイト・ユニバーシティ・リサーチ・ファウンデイション 慢性リンパ球性白血病におけるｍｉＲ−２９およびｍｉＲ−１８１によって制御されるＴＣＬ１発現
CA2663962A1 (en) * 2006-09-19 2008-03-27 Asuragen, Inc. Mir-15, mir-26, mir-31,mir-145, mir-147, mir-188, mir-215, mir-216, mir-331, mmu-mir-292-3p regulated genes and pathways as targets for therapeutic intervention
CA2667617A1 (en) * 2006-11-01 2008-05-08 The Ohio State University Research Foundation Microrna expression signature for predicting survival and metastases in hepatocellular carcinoma
US8293684B2 (en) * 2006-11-29 2012-10-23 Exiqon Locked nucleic acid reagents for labelling nucleic acids
WO2008070082A2 (en) * 2006-12-04 2008-06-12 The Johns Hopkins University Stem-progenitor cell specific micro-ribonucleic acids and uses thereof
DK2104737T3 (da) * 2006-12-08 2013-05-27 Asuragen Inc Funktioner og formål for let-7 mikro-RNAer
EP2104735A2 (en) * 2006-12-08 2009-09-30 Asuragen, INC. Mir-21 regulated genes and pathways as targets for therapeutic intervention
CN101622349A (zh) * 2006-12-08 2010-01-06 奥斯瑞根公司 作为治疗性干预靶标的miR-21调节的基因和途径
EP2104734A2 (en) * 2006-12-08 2009-09-30 Asuragen, INC. Mir-20 regulated genes and pathways as targets for therapeutic intervention
CA2671270A1 (en) * 2006-12-29 2008-07-17 Asuragen, Inc. Mir-16 regulated genes and pathways as targets for therapeutic intervention
CN101627134B (zh) * 2007-01-31 2013-11-06 俄亥俄州立大学研究基金会 用于急性髓细胞白血病（aml）的诊断、预后和治疗的基于微rna的方法和组合物
US20100144850A1 (en) * 2007-04-30 2010-06-10 The Ohio State University Research Foundation Methods for Differentiating Pancreatic Cancer from Normal Pancreatic Function and/or Chronic Pancreatitis
US20090005336A1 (en) * 2007-05-08 2009-01-01 Zhiguo Wang Use of the microRNA miR-1 for the treatment, prevention, and diagnosis of cardiac conditions
US20090131354A1 (en) * 2007-05-22 2009-05-21 Bader Andreas G miR-126 REGULATED GENES AND PATHWAYS AS TARGETS FOR THERAPEUTIC INTERVENTION
WO2008154098A2 (en) * 2007-06-07 2008-12-18 Wisconsin Alumni Research Foundation Reagents and methods for mirna expression analysis and identification of cancer biomarkers
US8053186B2 (en) * 2007-06-15 2011-11-08 The Ohio State University Research Foundation Oncogenic ALL-1 fusion proteins for targeting Drosha-mediated microRNA processing
ES2570359T3 (es) * 2007-08-03 2016-05-18 Univ Ohio State Res Found Regiones ultraconservadas que codifican ARNnc
US20090061424A1 (en) * 2007-08-30 2009-03-05 Sigma-Aldrich Company Universal ligation array for analyzing gene expression or genomic variations
US20090123933A1 (en) * 2007-11-12 2009-05-14 Wake Forest University Health Sciences Microrna biomarkers in lupus
WO2009070805A2 (en) * 2007-12-01 2009-06-04 Asuragen, Inc. Mir-124 regulated genes and pathways as targets for therapeutic intervention
US20090192114A1 (en) * 2007-12-21 2009-07-30 Dmitriy Ovcharenko miR-10 Regulated Genes and Pathways as Targets for Therapeutic Intervention

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044466A1 (en) 1999-12-16 2001-06-21 Women's And Children's Hospital Oxidoreductase gene associated with the fra16d fragile site

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CANCER RESEARCH, vol. 63, no. 22, pages 8068 - 8073
CANCER RESEARCH, vol. 63, no. 4, pages 878 - 881
ONCOGENE, vol. 24, no. 9, pages 1625 - 1633
See also references of EP1940456A4

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8349560B2 (en) 2007-06-15 2013-01-08 The Ohio State University Research Method for diagnosing acute lymphomic leukemia (ALL) using miR-222
US9085804B2 (en) 2007-08-03 2015-07-21 The Ohio State University Research Foundation Ultraconserved regions encoding ncRNAs
US8916533B2 (en) 2009-11-23 2014-12-23 The Ohio State University Materials and methods useful for affecting tumor cell growth, migration and invasion
US8946187B2 (en) 2010-11-12 2015-02-03 The Ohio State University Materials and methods related to microRNA-21, mismatch repair, and colorectal cancer
US10758619B2 (en) 2010-11-15 2020-09-01 The Ohio State University Controlled release mucoadhesive systems
US11679157B2 (en) 2010-11-15 2023-06-20 The Ohio State University Controlled release mucoadhesive systems
US8664192B2 (en) 2011-03-07 2014-03-04 The Ohio State University Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer
US9249468B2 (en) 2011-10-14 2016-02-02 The Ohio State University Methods and materials related to ovarian cancer
US9481885B2 (en) 2011-12-13 2016-11-01 Ohio State Innovation Foundation Methods and compositions related to miR-21 and miR-29a, exosome inhibition, and cancer metastasis
US8859202B2 (en) 2012-01-20 2014-10-14 The Ohio State University Breast cancer biomarker signatures for invasiveness and prognosis
US9434995B2 (en) 2012-01-20 2016-09-06 The Ohio State University Breast cancer biomarker signatures for invasiveness and prognosis

Also Published As

Publication number Publication date
WO2007044413A3 (en) 2007-11-08
EP1940456A4 (en) 2009-10-21
CN101312740A (zh) 2008-11-26
CA2624531A1 (en) 2007-04-19
AU2006302496A1 (en) 2007-04-19
US20090270484A1 (en) 2009-10-29
JP2009511482A (ja) 2009-03-19
EP1940456A2 (en) 2008-07-09

Similar Documents

Publication Publication Date Title
US20090270484A1 (en) WWOX Vectors and Uses in Treatment of Cancer
EP1002103B1 (en) A human glandular kallikrein enhancer, vectors comprising the enhancer and methods of use thereof
JP6072414B2 (ja) 腫瘍選択的ｅ１ａおよびｅ１ｂ変異体
Trapasso et al. Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells
US7319033B2 (en) Adenovirus vectors specific for cells expressing androgen receptor and methods of use thereof
AU751259B2 (en) Selective killing and diagnosis of p53+ neoplastic cells
Jounaidi et al. Use of replication-conditional adenovirus as a helper system to enhance delivery of P450 prodrug-activation genes for cancer therapy
KR20130015270A (ko) 종양 특이적 프로모터 및 이를 포함하는 종양살상 바이러스 벡터
Mathis et al. Cancer‐specific targeting of an adenovirus‐delivered herpes simplex virus thymidine kinase suicide gene using translational control
Li et al. Potent antitumor efficacy of an E1B 55kDa‐deficient adenovirus carrying murine endostatin in hepatocellular carcinoma
US6703375B2 (en) Molecular chemotherapy enhancement of radiotherapy
AU2019232768B2 (en) Treatment of tumors by a combination of an oncolytic adenovirus and a CDK4/6 inhibitor
Doloff et al. Dual E1A oncolytic adenovirus: targeting tumor heterogeneity with two independent cancer-specific promoter elements, DF3/MUC1 and hTERT
Numnum et al. Improved anti-tumor therapy based upon infectivity-enhanced adenoviral delivery of RNA interference in ovarian carcinoma cell lines
Doloff et al. Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions
CA2323235A1 (en) Adenoviral vectors for treating disease
CA2206205A1 (en) Tissue-specific treatment, diagnostic methods, and compositions using replication-deficient vectors
Hsieh et al. Gene therapy for bladder cancer using E1B-55 kD-deleted adenovirus in combination with adenoviral vector encoding plasminogen kringles 1–5
US20220354911A1 (en) Treatment of tumors by a combination of an oncolytic adenovirus, a cdk4/6 inhibitor and a further therapeutically active agent
RU2835886C1 (ru) Лечение опухолей комбинацией онколитического аденовируса, ингибитора cdk4/6 и дополнительного терапевтического агента
Majhen et al. Vincristine-resistant human laryngeal carcinoma cells demonstrate increased Rous sarcoma virus promoter activity
US8263398B2 (en) Promoter and viral vector containing the same
US20040146856A1 (en) Anti-neoplastic viral agents
Abbas UNDERSTANDING THE RELATIONSHIP BETWEEN ONCOLYTIC AD5 DELETED E1b55KDA LYTIC INFECTION AND P53 IN MAMMALIAN CELLS
Jacobsen et al. Advances in Gene Therapy for Bladder Cancer

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680043612.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2624531

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2008534659

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2006302496

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2006825457

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2006302496

Country of ref document: AU

Date of ref document: 20061004

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 12083067

Country of ref document: US