EP1828383A2 - Eif-5a spécifique de l'apoptose et polynucléotides codant pour un tel facteur - Google Patents

Eif-5a spécifique de l'apoptose et polynucléotides codant pour un tel facteur

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Publication number
EP1828383A2
EP1828383A2 EP05853235A EP05853235A EP1828383A2 EP 1828383 A2 EP1828383 A2 EP 1828383A2 EP 05853235 A EP05853235 A EP 05853235A EP 05853235 A EP05853235 A EP 05853235A EP 1828383 A2 EP1828383 A2 EP 1828383A2
Authority
EP
European Patent Office
Prior art keywords
apoptosis
cells
specific eif
expression
eif
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Withdrawn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
EP05853235A
Other languages
German (de)
English (en)
Inventor
John E. Thompson
Bruce C. Galton
Charles Dinarello
Adrienne Boone
Catherine Taylor
Leonid Reznikov
Marianne Hopkins
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.)
Eloxx Pharmaceuticals Inc
Original Assignee
Senesco Technologies Inc
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 Senesco Technologies Inc filed Critical Senesco Technologies Inc
Priority to EP07076075A priority Critical patent/EP1959010A3/fr
Publication of EP1828383A2 publication Critical patent/EP1828383A2/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • C07K14/4747—Apoptosis related proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.

Definitions

  • Pro-apoptotic proteins such as Bax or Bak
  • caspase-activating molecules such as mitochondrial cytochrome c
  • Anti-apoptotic proteins such as Bcl-2, promote cell survival by antagonizing the activity of the pro-apoptotic proteins, Bax and Bak. Tsujimoto (1998) Genes Cells, 3, 697-707; Kroemer (1997)
  • Figure 2 depicts the nucleotide sequence (SEQ ID NO: 15) and derived amino acid sequence (SEQ ID NO: 16) of the 5' end of rat apoptosis-specific eIF-5A cDNA.
  • Figure 8 is an alignment of the derived full-length amino acid sequence of rat corpus luteum apoptosis-specific eIF-5A (SEQ ID NO: 2) with the derived amino acid sequence of human eIF-5A (SEQ ID NO: 21) (Accession number BC000751 or NM_001970).
  • Figure 28a and b show the nucleotide alignment (SEQ ED NO: 41 and 42, respectively in order of appearance) and amino acid alignment (SEQ ID NO: 43 and 22, respectively in order of appearance) of human apoptosis-specific eIF-5A against human proliferating eIF-5A.
  • Figure 29 depicts the design of siRNAs against apoptosis-specific eIF-5A.
  • the siRNAs have the SEQ ID NO: 45, 48, 51, 54 and 56.
  • the full-length nucleotide sequence is shown in SEQ ID NO: 29.
  • Figure 57 is a Coomassie-blue-stained protein blot and the corresponding Western blot of COS-7 cells transiently transfected with pHM6 containing full-length rat apoptosis- specific eIF-5A in the sense orientation when p53 is used as a probe.
  • Figure 60 is a bar graph showing that both apoptosis-specific eIF-5 A and proliferation eIF-5 A are expressed in heart tissue.
  • the heart tissue was taken from patients receiving valve replacements.
  • Gene expression levels of apoptosis-specific eIF-5A (light gray bar) are compared to proliferation eIF-5A (dark gray bar).
  • the X-axis is patient identifier numbers.
  • Figure 84 and 85 show a decrease in the percentage of cells undergoing apoptosis in the cells having being treated with antisense apoptosis-specific eIF-5A oligonucleotides as compared to cells not having been transfected with the antisense apoptosis-specific eEF- 5A oligonucleotides.
  • Figure 91 is a characterization of lamina cribrosa cells by immunofluorescence.
  • Variant peptides include naturally occurring variants as well as those manufactured by methods well known in the art. Such variants can readily be identified/made using molecular techniques and the sequence information disclosed herein. Further, such variants can readily be distinguished from other proteins based on sequence and/or structural homology to the eBF-5A of the present invention. The degree of homology/identity present will be based primarily on whether the protein is a functional variant or non-functional variant, the amount of divergence present in the paralog family and the evolutionary distance between the orthologs. Non-naturally occurring variants of the eIF-5A polynucleotides, antisense oligonucleotides, or proteins of the present invention can readily be generated using recombinant techniques.
  • Antisense oligonucleotides have been used successfully in animal models of eye disease. In a model of transient global retinal ischemia, expression of caspase 2 was increased during ischemia, primarily in the inner nuclear and ganglion cell layers of the retina. Suppression of caspase using an antisense oligonucleotide led to significant histopathologic and functional improvement as determined by electroretinogram. Singh et al., (2001) J. Neurochem., 77(2), 466-75.
  • IFN- ⁇ Interferon gamma
  • NK natural killer
  • T lymphocytes which plays a central role in the cytokine network.
  • IFN- ⁇ induces a variety of responses in sensitive cells including anti-viral, anti-proliferative, and immuno- regulatory activity. Binding of EFN- ⁇ to its receptor (IFN- ⁇ R) leads to autophosphorylation of the Janus kinases JAKl and JAK2.
  • HT-29 cells transfected with siRNAs against apoptosis-eEF-5A show a decrease in apoptosis after being exposed to IFN- ⁇ and TNF- ⁇ . See figure 109.
  • apoptosis-specific eIF-5A is regulating IFN- ⁇ signaling through the JAK-STAT pathway. Interfering with apoptosis-specific eIF-5A expression therefore prevents IFN- ⁇ stimulated upregulation of TLR4 (which is required for colon epithelial cells to detect LPS) and the cells thus remain hyporesponsive to LPS. As a result, NFKB p50 is not activated in response to LPS binding by TLR4 and cytokine production (TNF- ⁇ and IL-8) is inhibited.
  • mice were similarly treated with siRNAs directed against apoptosis-specific eIF-5A.
  • Lipopolysaccharide (LPS) was administered to the mice to induce inflammation and an immune system response.
  • LPS kills thymocytes, which are important immune system precursor cells created in the thymus to fend off infection.
  • using the siRNAs directed against apoptosis- specific eEF-5A allowed approximately 90% survivability of the thymocytes in the presence of LPS.
  • thymocytes are destroyed, since they are precursors to T cells, the body's natural immunity is compromised by not being able to produce T cells and thus can't ward off bacterial infections and such.
  • siRNAs against apoptosis- specific eIF-5A can be used to reduce inflammation (as shown by a lower level of MPO in the first example) without destroying the body's natural immune defense system.
  • Sepsis is a very complex sequence of events and much work still needs to be done to completely understand how a patient goes from SIRS to septic shock.
  • Patients with septic shock have a biphasic immunological response. Initially they manifest an overwhelming inflammatory response to the infection. This is most likely due to the pro- inflammatory cytokines Tumor Necrosis Factor (TNF), IL-I, IL- 12, Interferon gamma (IFNgamma), and IL-6.
  • TNF Tumor Necrosis Factor
  • IL-I Interferon gamma
  • IFNgamma Interferon gamma
  • IL-6 Interferon gamma
  • eIF5Al has been reported to enter the nucleus only by passive diffusion 31 ' 38"39 .
  • evidence is provided here of regulated nuclear import of eIF5Al under conditions which are associated with apoptosis induced by death receptor activation or genotoxic stress.
  • ncrea ' sed levels ofunK ' ypusinated eIF5Al have been correlated with the induction of apoptosis 2 ' 19 ' 24 ' 40"43 .
  • the isolated DNA was end-labeled by incubating 500 ng of DNA with 0.2 ⁇ Ci [ ⁇ - 32 P]dCTP, 1 mM Tris, 0.5 rnM EDTA, 3 units of Klenow enzyme, and 0.2 pM each of d ATP, dGTP, and dTTP at room temperature for 30 minutes. Unincorporated nucleotides were removed by passing the sample through a 1 ml Sepadex G-50 column according to Sambrook et al. The samples were then resolved by Tris-acetate-EDTA (1.8 %) gel electrophoresis. The gel was dried for 30 minutes at room temperature under vacuum and exposed to x-ray film at - 80° C for 24 hours.
  • guanidinium buffer 4 M guanidinium isothiocyanate, 2.5 mM NaOAc pH 8.5, 0.8% /3-mercaptoethanol
  • the full-length coding sequence of rat apoptosis-specific eEF-5A and the 3' UTR of rat apoptosis-specific eIF-5A were amplified by PCR from the original rat eIF-5A RT-PCR fragment in pBluescript (SEQ ID NO:1).
  • the primers used were as follows: Forward 5' GCCAAGCTTAATGGCAGATGATTT GG 3' (SEQ ID NO: 59) (Hind3) and Reverse 5' CTGAATTCCAGT TATTTTGCCATGG 3' (SEQ ID NO:60) (EcoRl).
  • the monoclonal antibody to p53 was used at a dilution of 0.1 ⁇ g/ml, and the monoclonal antibodies to Bcl-2 and c- Myc were both used at a dilution of 0.83 ⁇ g/ml. After incubation with primary antibody for 60 to 90 minutes, the membrane was washed 3 times for 15 minutes in PBS-T. Secondary antibody was then diluted in 1 % milk in PBS and incubated with the membrane for 60 to 90 minutes. When p53 (Ab-6) was used as the primary antibody, the secondary antibody used was a goat anti-mouse IgG conjugated to alkaline phosphatase (Rockland) at a dilution of 1 : 1000.
  • Figure 58-A-E illustrate the dependence of p53 upregulation upon the expression of pHM6-full length rat apoptosis-specificeEF-5A in COS-7 cells. More rat apoptosis- specificeIF-5 A is detectable in the first transfection than in the second transfection.
  • the panel illustrates a corresponding Coomassie- blue-stained protein blot and the panel illustrates the Western blot with p53.
  • RKO cells were transfected with antisense oligonucleotides using the transfection reagent, Oligofectamine (Invitrogen). Twenty four hours prior to transfection, the cells were split onto a 24 well plate at 157,000 per well in MEM media supplemented with 10 % FBS but lacking penicillin/streptomycin. Twenty four hours later the cells had generally reached a confluency of approximately 50%. RKO cells were either mock transfected, or transfected with 100 nM or 200 nM of antisense oligonucleotide.
  • Transfection of lamina cribrosa cells was also tested using 100 and 200 nM antisense oligonucleotide and Oligofectamine using the same procedure described for RKO cells.
  • effective transfection of lamina cribrosa cells was achieved by simply adding antisense oligonucleotide, diluted from 1 ⁇ M to 10 ⁇ M in serum-free media, to the cells for 24 hours and thereafter replacing the media with fresh antisense oligonucleotides diluted in serum-containing media every 24 hours for a total of two to five days.
  • An anti- ⁇ -actin antibody (Oncogene) was also used to demonstrate equal loading of protein.
  • the monoclonal antibody to p53 was used at a dilution of 0.05 ⁇ g/ml
  • the antibody against apoptosis-specific eIF-5A was used at a dilution of 1 : 1000
  • the antibody against actin was used at a dilution of 1 :20,000.
  • the membrane was washed 3 times for 15 minutes in 0.05% Tween-20/PBS. Secondary antibody was then diluted in 1 % milk in 0.025 % Tween-20/PBS and incubated with the membrane for 60 to 90 minutes.
  • LPS lipopolysaccharide
  • IFN ⁇ interferon ⁇
  • fFN ⁇ interferon ⁇
  • Samples were collected before stimulator addition (72h), and at various times after addition as outlined in figure 131.
  • the media from each well was transferred to clean microcentrifuge tubes and cleared of any debris by centrifugation at 13000 x g for 3 mins. The media was stored at -20°C in 200-250 ul aliquots prior to analysis.
  • the total RNA was reverse transcribed using the following conditions:

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Abstract

La présente invention a trait à un facteur d'initiation eucaryote 5A (elF-5A), désigné elF-5A ou elF-5A1 spécifique de l'apoptose, à des acides nucléiques et des polypeptides ainsi qu'à des procédés pour l'accroissement ou la réduction de l'expression d'elF-5A spécifique de l'apoptose. L'invention a également trait à des procédés d'accroissement ou de réduction de l'apoptose.
EP05853235A 2004-12-03 2005-12-05 Eif-5a spécifique de l'apoptose et polynucléotides codant pour un tel facteur Withdrawn EP1828383A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07076075A EP1959010A3 (fr) 2004-12-03 2005-12-05 Eif-5A spécifique de l'apoptose et polynucléotides codant pour un tel facteur

Applications Claiming Priority (5)

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US63251404P 2004-12-03 2004-12-03
US66662605P 2005-03-31 2005-03-31
US67588405P 2005-04-29 2005-04-29
US71139705P 2005-08-26 2005-08-26
PCT/US2005/044266 WO2006060823A2 (fr) 2004-12-03 2005-12-05 Eif-5a spécifique de l'apoptose et polynucléotides codant pour un tel facteur

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EP1828383A2 true EP1828383A2 (fr) 2007-09-05

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EP07076075A Withdrawn EP1959010A3 (fr) 2004-12-03 2005-12-05 Eif-5A spécifique de l'apoptose et polynucléotides codant pour un tel facteur
EP05853235A Withdrawn EP1828383A2 (fr) 2004-12-03 2005-12-05 Eif-5a spécifique de l'apoptose et polynucléotides codant pour un tel facteur

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EP (2) EP1959010A3 (fr)
JP (1) JP2008522591A (fr)
KR (1) KR20070077225A (fr)
AR (1) AR051786A1 (fr)
AU (1) AU2005311586A1 (fr)
CA (1) CA2588129A1 (fr)
IL (1) IL183585A0 (fr)
NZ (1) NZ556236A (fr)
TW (1) TW200634154A (fr)
WO (1) WO2006060823A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007109674A2 (fr) * 2006-03-20 2007-09-27 Senesco Technologies, Inc. Utilisation d'arnsi eif-5a spécifique de l'apoptose pour la régulation négative de l'expression de cytokines pro-inflammatoires afin de traiter la septicémie
US8703929B2 (en) * 2008-03-07 2014-04-22 Senesco Technologies, Inc. Compositions comprising siRNA and plasmids
JP5578522B2 (ja) * 2008-05-27 2014-08-27 義規 世古 アポトーシス誘導薬
JP2012501650A (ja) * 2008-09-03 2012-01-26 セネスコ テクノロジーズ，インコーポレイティド 癌細胞にアポトーシスを誘導するための切断型ｅｉｆ−５ａ１ポリヌクレオチドの使用
JP5302054B2 (ja) * 2009-03-06 2013-10-02 オリンパス株式会社 Ｄｎａが断片化されたアポトーシス細胞の検出方法、細胞画像解析装置、及びプログラム
FR2962906A1 (fr) 2010-07-20 2012-01-27 Univ Nice Sophia Antipolis UTILISATION DES INHIBITEURS DE L'HYPUSINYLATION DE eIF5A POUR TRAITER LES PATHOLOGIES ISCHEMIQUES ET HYPOXIQUES

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Publication number Priority date Publication date Assignee Title
US7166467B2 (en) * 2001-07-23 2007-01-23 Senesco Technologies, Inc. Nucleic acids, polypeptides, compositions, and methods for modulating apoptosis
US7968523B2 (en) * 2001-07-23 2011-06-28 Senesco Technologies, Inc. Method for inducing apoptosis using apoptosis-specific EIF5-A
US7217517B2 (en) * 2001-07-23 2007-05-15 Senesco Technologies, Inc. Nucleic acids, polypeptides, and methods for modulating apoptosis
JP2006520611A (ja) * 2003-03-05 2006-09-14 セネスコ テクノロジーズ，インコーポレイティド ｅＩＦ−５Ａ１の発現を抑制するための、アンチセンス・オリゴヌクレオチド又はｓｉＲＮＡの使用
TW200512293A (en) * 2003-06-06 2005-04-01 Senesco Technologies Inc Inhibition of apoptosis-specific eIF-5A ("eIF-5A1") with antisense oligonucleotides and siRNAs as anti-inflammatory therapeutics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006060823A2 *

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JP2008522591A (ja) 2008-07-03
CA2588129A1 (fr) 2006-06-08
AR051786A1 (es) 2007-02-07
AU2005311586A1 (en) 2006-06-08
EP1959010A2 (fr) 2008-08-20
WO2006060823A2 (fr) 2006-06-08
WO2006060823A3 (fr) 2007-02-22
TW200634154A (en) 2006-10-01
EP1959010A3 (fr) 2009-02-25
IL183585A0 (en) 2008-04-13
KR20070077225A (ko) 2007-07-25
NZ556236A (en) 2009-12-24

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