EP1573008A2 - Polynucleotides diriges contre la htert et utilisation de ces derniers - Google Patents

Polynucleotides diriges contre la htert et utilisation de ces derniers

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Publication number
EP1573008A2
EP1573008A2 EP03785567A EP03785567A EP1573008A2 EP 1573008 A2 EP1573008 A2 EP 1573008A2 EP 03785567 A EP03785567 A EP 03785567A EP 03785567 A EP03785567 A EP 03785567A EP 1573008 A2 EP1573008 A2 EP 1573008A2
Authority
EP
European Patent Office
Prior art keywords
polynucleotide
tumor
therapy
use according
carcinoma
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Withdrawn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
EP03785567A
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German (de)
English (en)
Inventor
Bernd Schwenzer
Uta Schmidt
Manfred P. Wirth
Kai KRÄMER
Susanne FÜSSEL
Axel Meye
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.)
Technische Universitaet Dresden
Original Assignee
Technische Universitaet Dresden
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Filing date
Publication date
Priority claimed from DE10306084A external-priority patent/DE10306084A1/de
Application filed by Technische Universitaet Dresden filed Critical Technische Universitaet Dresden
Publication of EP1573008A2 publication Critical patent/EP1573008A2/fr
Withdrawn legal-status Critical Current

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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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1241—Nucleotidyltransferases (2.7.7)

Definitions

  • the present invention relates to polynucleotides which are directed against a gene of a catalytic subunit of human telomerase (hTERT) and to the use of these polynucleotides for the diagnosis, prophylaxis, treatment, monitoring of diseases associated with cell growth, differentiation and / or division , such as tumor diseases.
  • hTERT human telomerase
  • telomeres Chromosome ends are responsible, among other things, for controlling the ability of proliferation and thus for the aging of cells [Harley]. The structure of these telomeres has been studied in numerous living systems.
  • RNA component hTR
  • hTERT catalytic subunit
  • telomere activity was detected in immortalized cell lines and in> 85% of the tumors examined [Kim et al. ]. This correlates with the expression of the hTERT component, as has been shown in bladder cancer [Ito et al. ]. There is also a connection between the level of hTERT expression in bladder carcinoma and the clinical course of the tumor disease (de Kok et al.). Therefore, human telomerase is an ideal target for the diagnosis and treatment of human diseases associated with cellular proliferation. such as cancer, methods for diagnosing and treating cancer and other diseases associated with telomerase are disclosed, inter alia, in US 5,489,508 or US 5,645,986.
  • telomere activity has been shown as a specific way to therapeutically control tumor cells described. Important efforts to modify the activity of telomerase in the context of cancer are disclosed in EP 666313, WO 97/37691, WO 99/50279, US 2002/0045588 AI or WO 98/28442. Such general teachings do not reveal to the skilled person specific teachings on technical action.
  • a substance or a molecule that interacts with the entire sequence region coding for hTERT leads to a reduction in the corresponding telomerase activity, for example in a cell culture, but such substances are not suitable for application in organisms, since they usually are much too large and are attacked and destroyed by the immune system of the organism in question. In addition, a large number of undesirable interactions or side effects can occur. It was therefore an object of the invention to provide alternative compact molecules which have a simple and effective inhibitory interaction with selected, specific structural units which encode the telomerase.
  • hTERT is directed, wherein the polynucleotide specifically interacts with primary structures of this hTERT mRNA in two target sequence regions from 2176 to 2250 and 2296 to 2393 according to the gene database entry AF 015950.
  • the numbers represent - also in the following sections - the corresponding nucleotide positions within the hTERT mRNA (total length 4015 nucleotides).
  • the invention thus relates to the surprising teaching that against tumor-associated abnormal hTERT-mRJ-IA expression onsmus ⁇ -.er suw-.e telomerase activity levels by a possible hTER inhibition with the polynucleotides according to the invention.
  • polynucleotides are directed against defined hTERT mRNA sequence motifs in the range from 2000 to 2500. They can be biological and / or chemical structures that are able to interact with the target sequence area in such a way that a specific recognition / binding and interaction can be determined. Examples of polynucleotides can in particular be nucleic acid constructs and their derivatives. Of course, it is also possible to use other recognition molecules instead of or in combination with the polynucleotides, such as, for. B. antibodies, lectins, affilines, aptamers, chelators and others.
  • the polynucleotide specifically interacts with two target sequence regions 2176 to 2250 and 2296 to 2393.
  • particularly efficient hTERT inhibition is possible in these sequence regions.
  • shorter areas with changes within these target sequences or with changed edge areas or different derivatizations / modifications / fusions / complexations which can also be combined and / or coupled with other recognition molecules such as polynucleotides.
  • target sequence regions make it possible for the person skilled in the art to provide, in particular, very small and / or compact polynucleotides that essentially do not interact with other structures, in particular immunological defense structures, within the cell tissue or the organism or are attacked by them, but rather can specifically interact with the target sequence region of the hTERT mRNA.
  • the sequence region or the recognition molecule in particular the polynucleotide, is modified by addition, amplification, inversion, missense mutation, nonsense mutation, point mutation, deletion and / or substitution.
  • modifications can, for example, result in the polynucleotide binding to the mRNA of the hTERT catalytic subunit with a higher avidity or specificity.
  • the polynucleotide binds with less specificity or avidity.
  • the mutations in the hTERT sequence region can be, for example, inheritable or non-inheritable changes.
  • the modifications can be such that they can be detected directly at the RNA level or at the DNA level.
  • the mutations can also include, for example, mutations in connection with a cytologically visible genome and / or chromosome mutations which are associated with changes in hTERT. Such mutations can arise from the fact that parts of the chromosome are lost, doubled, have the opposite orientation or are transferred to other chromosomes.
  • the mutation is only one or a few neighboring base pairs, as is the case with point mutation, for example. If, for example, a base pair is lost in the form of a deletion or if a base pair is additionally inserted, as in the insertion, the reading frame of the gene concerned shifts to a reading frame mutation.
  • substitution mutation in the sense of the invention, for example, one base is exchanged for another, the consequences resulting therefrom being different:
  • a codon can be converted into a synonymous codon
  • the mutation ends the translation at a specific point, and the hTERT fragments formed can be inactive or active.
  • the polynucleotide is a nucleic acid construct.
  • Nucleic acid constructs in the sense of the invention can be all structures which are essentially based on nucleic acids or whose active center is essentially based on nucleic acids.
  • the polynucleotide can be part of complexes or formulations consisting of lipids, carbohydrates or proteins or peptides, for example in the form of a nanocapsule. This complex or formulation comprises an area which contains nucleic acids which can interact with hTERT.
  • the specialist Various ways are known to provide such constructs.
  • the nucleic acid construct is an antisense (AS) oligonucleotide (ON), a DNAzyme, a ribozyme, an siRNA and / or a peptide nucleic acid (PNA).
  • AS antisense
  • ON oligonucleotide
  • PNA peptide nucleic acid
  • AS constructs are synthetically produced molecules that enable selective inhibition of the biosynthesis of selected proteins. For example, ON, PNAs, ribozymes, DNAzymes are used.
  • the AS effect is based on the sequence-specific hybridization of the ' constructs by Watson-Crick base pairing with the target mRNA coding for the protein to be repressed, which leads to the prevention of protein synthesis via various mechanisms (Table 1).
  • Tab. 1 AS effects and their mechanisms of action ss - "Single stranded" (single strand)
  • AS-ON as therapeutic substances represents, in addition to various other application fields, a new promising therapy concept for oncological diseases [Tamm et al. ]. While conventional chemotherapy leads to non-specific inhibition of cell proliferation, AS therapy specifically inactivates those mRNAs that represent the molecular basis or an essential component of the degenerate, deregulated growth and tumor progression, and for the inhibition of the body's immune defense can be responsible.
  • AS-ON differ from other therapeutic agents, such as antibodies, toxins or immunotoxins, in that they are relatively small molecules with a molecular weight of usually about 5 kDa.
  • the small size of the AS-ON enables good tissue penetration.
  • tumor blood vessels in contrast to blood vessels of normal tissue, are permeable to substances in a size range between 4-10 kDa. This means that therapeutic AS-ON can specifically penetrate tumor blood vessels.
  • Another advantage of these substances for example compared to antibodies that are almost exclusively active against extracellular proteins, is that, in principle, all proteins, both cytoplasmic and nucleus-localized as well as membrane-bound proteins, can be attacked via the respective target mRNA.
  • the phosporthioat-AS-ON which is relatively resistant to a nuclease attack, is currently being evaluated in a number of clinical studies (phase I-III) with regard to its potential as anti-cancer therapeutics.
  • Target mRNA molecules that are overexpressed in tumors are attacked.
  • non-AS phosphothioate-ON
  • a partial terminal modification of ON constructs offers increased stability in the extra- and intracellular milieu of the target cells (protection against degradation by exonucleases), especially when applied in vivo.
  • a positive side effect that has been observed when using PS-ON is its immunostimulatory effect, which can support possible therapeutic success in some tumor applications.
  • ribozymes As catalytically active RNA molecules, ribozymes are able to recognize cellular RNA structures as substrates and cleave them sequence-specifically at a phosphorus diester bond. The detection takes place via AS arms, which enable hybridization with the target mRNA due to complementary sequences. Compared to AS-ON, ribozymes have the fundamental advantage that a ribozyme molecule as a real catalyst has a large number of identical ones
  • Ribozymes are already there effective in much lower concentration than ON and also lead to irreversible RNA degradation due to substrate cleavage [Sun et al. ].
  • the hammerhead ribozyme (review: Birikh et al., 1997; Tanner, 1999) is particularly interesting for such applications because it can already be catalytically active as a comparatively small molecule (approx. 30-50 nucleotides).
  • a very effective trans-cleaving hammerhead ribozyme consists, for example, of only 14 conserved nucleotides in the catalytic domain and two variable stem sequences (advantageously each of 6-8 nucleotides), which by Watson-Crick base pairing (analogous to AS-ON) Realize sequence-specific recognition of the substrate to be cleaved and then inactivate it by cleaving a phosphorus diester bond.
  • a specific cleaving hammerhead ribozyme can be constructed against practically any RNA molecule that has a potential cleavage site with the minimal sequence requirement -NUX- and thus, for example, inhibit cellular mRNA or viral RNA.
  • Other catalytic nucleic acids from DNA-yp e.g. DNAzyme
  • DNAzyme can be used analogously.
  • RNAi RNA interference
  • siRNA small interference RNA
  • the ' siRNA constructs are associated with specific cellular proteins, followed by the recognition of the target mRNA sequence due to the complementarity of the AS-si RNA strand.
  • the intrinsic endonuclease activity of the ribonucleoprotein complex enables a specific degradation of the mRNA to be inhibited.
  • the AS-ON is a PS-ON or a nucleic acid construct modified with further chemical changes.
  • sequence region of the hTERT mRNA to which the polynucleotide is complementary is selected from the group comprising 2183-2205, 2206-2225, 2315-2334, 2317-2336, 2324-2346, 2331-2350 and / or 2333-2352.
  • Inhibition can be suppressed, among other diseases, such as tumors associated with the expression of this gene.
  • the polynucleotide is immobilized.
  • immobilization is understood to mean various methods and techniques for fixing the polynucleotides on specific supports.
  • the immobilization can be used, for example, to stabilize the polynucleotides, as a result of which they are used in particular during storage or with a single batch approach are not reduced by ⁇ biological, chemical or physical agents in their activity or adversely modified.
  • the immobilization of the polynucleotides enables repeated use under routine technical or clinical conditions; furthermore, the sample can be continuously reacted with the polynucleotides.
  • Polynucleotides are fixed together without their activity being adversely affected. As a result of the crosslinking, they are advantageously no longer soluble.
  • Binding to a carrier takes place, for example, by adsorption, ion binding or covalent binding. This can also take place within microbial cells or liposomes or other membrane-containing closed or open structures.
  • the polynucleotide is by fixation advantageously not influenced in its activity. It can advantageously be used multiple times or continuously, for example in the clinic, for diagnosis or therapy in a vehicle-bound manner.
  • inclusion takes place in the sense of the invention in particular in a semipermeable membrane in the form of gels, fibrils or fibers. Encapsulated polynucleotides are separated by a semipermeable membrane from the surrounding sample solution in such a way that they can advantageously still interact with the catalytic subunit of human telomerase or with fragments thereof.
  • immobilization such as. for example, adsorption on an inert or electrically charged inorganic or organic carrier.
  • Such carriers can be, for example, porous gels, aluminum oxide, concrete, agarose, starch, nylon or polyacrylamide.
  • the immobilization takes place here through physical binding forces, often with the participation of hydrophobic interactions and ionic bonds.
  • Such methods are advantageously easy to use and they influence the conformation of the polynucleotides only to a small extent.
  • the binding can advantageously be improved by electrostatic binding forces between the charged groups of the polynucleotides and the carrier, for example by using ion exchangers such as Sephadex.
  • Another method is covalent binding to carrier materials.
  • the carriers can be reactive Have groups that form homopolar bonds with amino acid side chains.
  • Suitable groups in polynucleotides are carboxy, hydroxyl and sulfide groups and in particular the terminal amino groups of lysines.
  • Aromatic groups offer the possibility of diazo couplings.
  • the surface of microscopic porous glass particles can be activated by treatment with silanes and then populated with polynucleotides. Hydroxy groups of natural polymers can be activated with bromocyan, for example, and then coupled with polynucleotides. Numerous polynucleotides can advantageously form direct covalent bonds with polyacrylamide resins.
  • the polynucleotides When enclosed in three-dimensional networks, the polynucleotides are enclosed in ionotrophic gels or other structures known to the person skilled in the art.
  • the pores of the matrix are in particular such that the polynucleotides are retained and an interaction with the target molecules is possible.
  • cross-linking the polynucleotides are cross-linked with bifunctional ones
  • Agents converted into polymeric aggregates are gelatinous and easily deformable and are particularly suitable for use in various reactors.
  • the mechanical and enzymatic properties can advantageously be improved by adding other inactive components, such as, for example, gelatin, during the crosslinking.
  • the reaction space of the polynucleotides is limited using membranes.
  • the microencapsulation can be carried out, for example, as an interfacial polymerization.
  • immobilized recognition molecules in particular polynucleotides, are all recognition molecules or polynucleotides which are in a state which permits their reuse.
  • the restriction of the mobility and the solubility of the polynucleotides by chemical, biological or physical means advantageously leads to low process costs.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the polynucleotides according to the invention, optionally in a combination with a pharmaceutically acceptable carrier.
  • This pharmaceutical carrier can in particular comprise additional substances and substances, such as medical and / or pharmaceutical-technical auxiliaries.
  • Medical auxiliaries are, for example, those substances which are used for production as ingredients of pharmaceutical compositions.
  • Pharmaceutical-technical auxiliaries are used for the suitable formulation of the pharmaceutical composition or the medicament and can even - if they are only required during the production process - be subsequently removed or can be part of the pharmaceutical composition as pharmaceutically acceptable carrier substances.
  • the pharmaceutical composition is optionally in combination with a pharmaceutically acceptable diluent. This can be, for example, phosphate-buffered saline,
  • Water, emulsions such as oil / water Emulsions, various types of detergents, sterile solutions and the like act.
  • the pharmaceutical composition can be administered, for example, in connection with gene therapy.
  • gene therapy is a form of treatment using natural or recombinantly modified nucleic acid constructs, individual gene sequences or entire gene or chromosome sections or coded transcript areas, their derivatives / modifications with the aim of biologically-based and selective inhibition or Reverting the disease symptoms and / or their causal causes, which in the special case means the inhibition of a target molecule overexpressed in the course of a disease at the nucleic acid level, in particular at the transcript level.
  • Gene therapy can also be carried out, for example, using suitable vectors, such as, for example, viral vectors and / or complexing with lipids or dendrimers.
  • gene therapy can also take place via packaging in protein casings.
  • the polynucleotide it is possible for the polynucleotide to be fused or complexed with another molecule which supports the directional transport to the target site, the uptake into and / or the distribution within the target cell.
  • the type of dosage and route of administration can be determined by the attending physician according to the clinical requirements. It is known to the person skilled in the art that the type of dosage depends on various factors, such as, for example
  • the invention also relates to a kit comprising the polynucleotide and / or the pharmaceutical composition. Furthermore, the invention also relates to an array comprising the polynucleotide and / or the pharmaceutical composition.
  • the kit and array can be used to diagnose and / or treat diseases associated with the function of the catalytic subunit of human telomerase.
  • the invention also relates to the use of the polynucleotide, the kit, the array for diagnosis, prophylaxis, reduction, therapy, follow-up and / or post-treatment of diseases related to cell growth, differentiation and / or division.
  • the disease associated with cell growth, differentiation and / or division is a tumor.
  • the tumor is particularly preferably a solid tumor and / or a
  • the tumors which may be of epithelial or mesodermal origin, can be benign or malignant types of cancer of the organs of the invention
  • the group of blood and Lymphdrüsenkrebsart of the invention are within the meaning all forms' of leukemias (for example, in connection with B cell leukemia, mixed-cell leukemia, null cell leukemia, T-cell leukemia, chronic T-cell leukemia , HTLV-II-associated leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, mast cell leukemia and myeloid leukemia) and lymphomas.
  • mesenchymal malignant tumors are: fibrosarcoma; the malignant histiocytoma; liposarcoma; hemangiosarcoma; chondrosarcoma and osteosarcoma; Ewing's sarcoma; leio and rhabdomyosarcoma, synovial sarcoma; Carcinosarcoma.
  • tumors As further types of tumors, which are also summarized in the sense of the invention under the term “neoplasms”, preferred are: bone neoplasms, breast neoplasms, neoplasms of the digestive system, colorectal neoplasms, liver neoplasms, pancreatic neoplasms, brain appendage neoplasms, testes -Neoplasms, orbital neoplasms, neoplasms of the head and neck, central nervous system, neoplasms of the ear organ, pelvis, respiratory tract and urogenital tract).
  • neoplasms preferred are: bone neoplasms, breast neoplasms, neoplasms of the digestive system, colorectal neoplasms, liver neoplasms, pancreatic neoplasms, brain appendage neoplasms, testes -Neoplasms, orbital ne
  • the cancer or the tumor that is treated or prevented is selected from the group: tumors of Ear, nose and throat area including tumors of the inner nose, paranasal sinuses, nasopharynx, lips, oral cavity, oropharynx, larynx, hypopharynx, ear, salivary glands and paragangliomas, lung tumors including non-small cell bronchial carcinomas , small cell bronchial carcinomas, tumors of the mediastinum, tumors of the gastrointestinal tract including tumors of the esophagus, stomach, pancreas, liver, gallbladder and biliary tract, small intestine, colon and rectal carcinomas and anal cancers, urogenital kidney tumors, including tumors of the ureter, kidney tumors, including tumors the bladder, prostate, urethra, penis and testes, gynecological tumors including tumors of the cervix, vagina, vulva, carcinoma of the group: tumors of E
  • the solid tumor is a tumor of the urogenital tract and / or the gastrointestinal tract.
  • the tumor is a colon carcinoma, a gastric carcinoma, a pancreatic carcinoma, a colon cancer, a small bowel cancer, an ovarian carcinoma, a cervical carcinoma, a lung cancer, a renal cell carcinoma, a brain tumor, a head and neck tumor Liver carcinoma and / or a metastasis of these tumors / carcinomas.
  • the solid tumor is a breast, bronchial, colorectal and / or prostate carcinoma.
  • the tumor of the urogenital tract is a bladder carcinoma (BCa).
  • BCa bladder carcinoma
  • the BCa is the fourth most common form of cancer and the seventh most common cancer death in the Federal Republic of Germany.
  • TUR-B as a general primary therapy for BCa allows organ-preserving removal of superficial tumors. Despite this histopathologically defined complete removal of the tumor, a relatively high proportion of 50-70% of patients are affected by a relapse within two years [Stein et al. ].
  • a synchronous or metachronous multifocal occurrence of tumor foci represents a diagnosis and therapy problem, which may result in the occurrence of recurrences remote from the resected primary tumor location [Sidransky et al. ].
  • recurrence or tumors primarily classified as superficial, long-term prophylaxis with an immune (Bacillus Calmette-Guerin - BCG) or chemotherapeutic agent is usually carried out after TUR-B
  • the polynucleotide, the pharmaceutical composition, the kit and / or the array are used for a follow-up control, which essentially represents monitoring the effectiveness of an antitumor treatment.
  • the polynucleotide is used in a combination therapy, in particular for the treatment of tumors.
  • the combination therapy comprises chemotherapy, cytostatic treatment and / or radiation therapy.
  • the combination therapy is an adjuvant, biologically specified form of therapy. It is very particularly preferred that this form of therapy is an immunotherapy.
  • the combination therapy is a gene therapy and / or a
  • a polynucleotide against the same or a different target molecule Various combination therapies, in particular for the treatment of tumors, are known to the person skilled in the art. It can be provided, for example, that cytostatic treatment takes place within a combination therapy or, for example, radiation of a specific tumor area, this treatment being combined with gene therapy, the polynucleotide according to the invention being used as an anti-cancer agent. However, the polynucleotide according to the invention can also be used in combination with other polynucleotides can be used against the same or a different target molecule. Accordingly, it can be particularly preferred that the polynucleotide is used to increase the sensitivity of tumor cells to 'cytostatic and / or radiation. It is further preferred that the polynucleotide is used to inhibit the vitality, the proliferation rate of cells and / or to induce apoptosis and cell cycle arrest.
  • the easily transfectable human urinary bladder carcinoma line EJ28 showed, after transfection, in particular when using five specific anti-hTERT-AS constructs (cf. Table 2), an immediate and continuous reduction in their viability by more than 65% compared to that
  • Nonsense (NS) control (Fig. 2). It was particularly noticeable that four of the most effective constructs were directed against a single mRNA sequence motif.
  • BCa cell line 5637 was able to significantly increase the viability-inhibiting effect of the chemotherapeutic agent with the AS-ON constructs AStel2206 and AStel2331 Detect cisplatin in two different doses (Fig. 5).
  • the name contains the sequence area of the hTERT mRNA (Acc. No.: AF015950), to which the respective AS-ON is complementary; 2
  • the motifs depicted each contain 10 nt double-stranded RNA at the 5 'and 3'term;
  • nucleotides in bold represent the area in AS-ON. which is complementary to the actual SS region of the target motif.
  • Boiziau C Elector R, Cazenave C, Roig V, Thuong NT,
  • Crooke ST Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta (1999) 1489: 31-44.
  • Greider CW, Blackburn EH Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell (1985) 43: 405-13.
  • telomerase reverse transcriptase mRNA in urothelial cell carcinomas.

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Abstract

La présente invention concerne des polynucléotides dirigés contre un gène d'une sous-unité catalytique de la télomérase humaine ainsi que l'utilisation de ces polynucléotides dans le diagnostic, la prophylaxie, l'atténuation, le contrôle de l'évolution de maladies associées à la croissance cellulaire, la différenciation cellulaire et/ou la division cellulaire, telles que des maladies tumorales.
EP03785567A 2002-12-06 2003-12-08 Polynucleotides diriges contre la htert et utilisation de ces derniers Withdrawn EP1573008A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10258117 2002-12-06
DE10258117 2002-12-06
DE10306084 2003-02-07
DE10306084A DE10306084A1 (de) 2002-12-06 2003-02-07 Gegen hTERT gerichtete Erkennungsmoleküle und die Verwendung dieser
PCT/DE2003/004114 WO2004053116A2 (fr) 2002-12-06 2003-12-08 Polynucleotides diriges contre la htert et utilisation de ces derniers

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EP1573008A2 true EP1573008A2 (fr) 2005-09-14

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US (1) US20060127909A1 (fr)
EP (1) EP1573008A2 (fr)
AU (1) AU2003294653A1 (fr)
WO (1) WO2004053116A2 (fr)

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5645986A (en) * 1992-05-13 1997-07-08 Board Of Reagents, The University Of Texas System Therapy and diagnosis of conditions related to telomere length and/or telomerase activity
US5489508A (en) * 1992-05-13 1996-02-06 University Of Texas System Board Of Regents Therapy and diagnosis of conditions related to telomere length and/or telomerase activity
US6444650B1 (en) 1996-10-01 2002-09-03 Geron Corporation Antisense compositions for detecting and inhibiting telomerase reverse transcriptase
US6093809A (en) * 1996-10-01 2000-07-25 University Technology Corporation Telomerase
EP0917579A1 (fr) * 1997-07-01 1999-05-26 Cambia Biosystems LLC Genes et proteines telomerase de vertebres et leurs utilisations
US6608188B1 (en) * 1998-01-08 2003-08-19 Chugai Seiyaku Kabushiki Kaisha CRT-1 gene having reverse transcriptase motif
US6492171B2 (en) 2000-05-16 2002-12-10 Isis Pharmaceuticals, Inc. Antisense modulation of TERT expression
US20050153916A1 (en) * 2001-05-18 2005-07-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of telomerase gene expression using short interfering nucleic acid (siNA)
US20060257851A1 (en) * 2002-11-26 2006-11-16 Itzhak Bentwich Bioinformatically detectable group of novel viral regulatory genes and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004053116A2 *

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AU2003294653A8 (en) 2004-06-30
US20060127909A1 (en) 2006-06-15
WO2004053116A3 (fr) 2004-09-16
AU2003294653A1 (en) 2004-06-30

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