EP1326878A2 - Oligonucleotides, agents containing these oligonucleotides, and the use thereof - Google Patents
Oligonucleotides, agents containing these oligonucleotides, and the use thereofInfo
- Publication number
- EP1326878A2 EP1326878A2 EP01985701A EP01985701A EP1326878A2 EP 1326878 A2 EP1326878 A2 EP 1326878A2 EP 01985701 A EP01985701 A EP 01985701A EP 01985701 A EP01985701 A EP 01985701A EP 1326878 A2 EP1326878 A2 EP 1326878A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- oligonucleotide
- oligonucleotide according
- tocopheryl
- residue
- oligonucleotides
- 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- Withdrawn
Links
Classifications
-
- 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
- C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
-
- 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
- C12N2310/18—Type of nucleic acid acting by a non-sequence specific mechanism
-
- 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
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- 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
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
-
- 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
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
- C12N2310/3515—Lipophilic moiety, e.g. cholesterol
Definitions
- Oligonucleotides Oligonucleotides, agents containing them and their use
- the present invention relates to certain oligonucleotides, pharmaceutical compositions containing these oligonucleotides and their use.
- the oligonucleotides are particularly able to inhibit the proliferation of prancreatic tumors. These oligonucleotides therefore have a therapeutic potential for the treatment of pancreatic tumors. In the broadest sense, it can be an antisense therapy.
- ODN Modified oligodeoxyribonucleotides
- ASODN antisense oligodesocyribonucleotides
- Oligodeoxyribonucleotides that do not have the sequence of an ASODN have been reported.
- the present invention therefore relates to the oligonucleotides specified in the claims.
- oligonucleotide means an oligomer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. These include oligonucleotides, which consist of naturally occurring nucleobases, sugars and covalent internucleoside linkages (backbone), as well as oligonucleotides with parts that do not occur in nature, but whose function is similar. Such modified oligonucleotides are preferred over the native forms according to the invention because they have desired properties, for example an increased cellular uptake, an increased affinity for target nucleic acids and an increased stability in the presence of nucleases.
- nucleotides can have modifications or substitutions on the nucleobases (also simply referred to here as "base”).
- base also simply referred to here as "base”.
- the unmodified or natural nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U).
- Modified nucleobases include synthetic nucleobases such as 5-methylcytosine (5-Me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and 5-halocytosine, 5-propynyluracil and 5-propynylcytosine, 6-azouracil, 6-azocytosine and 6-azothymine, 5-uracil (pseudouracil), 4-thiouracil , 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo, especially 5-bromo, 5-trifluoromethyl and further 5-substituted uracils
- synthetic nucleobases such as 5-
- nucleobases are particularly useful for increasing binding affinity.
- These include 5-substituted pyrimidines, 6-azapyrimidines and N-2-, N-6- and O-6-substituted purines, for example 2-aminopropyladenine, 5-propynyl uracil and 5-propynyl cytosine.
- 5-methylcytosine increases the stability of a nucleic acid duplex by 0.6-1.2 ° C.
- Suitable according to the invention are C-rich oligonucleotides in which more than 40% and preferably more than 50% of the nucleobases are cytosine residues or mimetics thereof. Mimetics of cytosine residues are modified nucleobases in the above sense, which are similar
- Binding properties so above all the same specificity, but have different affinity for complementary nucleobases. The same applies to mimetics of other nucleobases.
- a proportion of guanine or mimetics thereof is appropriate according to the invention.
- oligonucleotides according to the invention have at least one GC or CG motif, i.e. at least one cytosine residue or a mimetic thereof is arranged in a consecutive sequence (sequence) to a guanine or a mimetic thereof.
- oligonucleotides according to the invention contain no adenine.
- the oligonucleotides according to the invention it is expedient for the oligonucleotides according to the invention to have 8 to 30, preferably 12 to 25 and in particular about 15 nucleobases.
- nucleobases in oligonucleotides according to the invention are generally ensured in that the nucleobases are suitably linked to one another.
- an oligomer results with a consecutive sequence of nucleobases (sequence) which are linked to one another via a backbone which forms the main chain. While linear oligomers are preferred, branched, cyclic or even cross-linked structures may also be suitable in certain cases.
- the oligonucleotides are usually linked nucleosides, i.e. Base-sugar combinations.
- the base part of the nucleotides is usually a heterocyclic base, in most cases a purine or a pyrimidine.
- the nucleosides are generally linked to one another by a group covalently bonded to the sugar part of the nucleoside. In those nucleosides which have a pentofuranosyl sugar, this group can be bound to either the 2'-, 3'- or 5'-hydroxyl group of the sugar. As a rule, these groups link covalently adjacent nucleosides to one another to form a linear, oligomeric compound.
- the respective ends of this linear, oligomeric structure can in turn be connected to one another to form circular structures.
- open, linear structures are preferred.
- the linking groups generally form the internucleoside backbone of the oligonucleotide.
- the normal linkage or backbone of RNA and DNA is 3'-5'-phosphodiester linkages, i.e. the linking groups are phosphate groups.
- oligonucleotides which have a modified backbone or non-natural internucleoside linkages.
- modified oligonucleotide backbones include phosphorothioates, partially or fully sulfurized, for example chiral phosphorothioates, phosphoromothioates and phosphorodithioates.
- Other modified backbones are phosphorus triesters, aminoalkylphosphotriesters, methyl and other alkylphosphonates, for example 3'-alkylenephosphonates and chiral phosphonates, phosphinates, phosphoramidates, for example 3'-aminophosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, Thionoalkylphosphonates, thionoalkylphosphotriesters and boronphosphates with normal 3'-5'-linkages, 2'-5'-linked analogues thereof, and those of opposite polarity, with the adjacent pairs of nucleoside units 3'-5 'to 5'-3' or 2'-5 'are linked to 5'-2'.
- Various salts are
- Special modified oligonucleotide backbones without a phosphorus atom are generally formed by short-chain alkyl or cycloalkyl internucleoside linkages, which can optionally also include heteroatoms or heterocycles. These include those with morpholino linkages (partially formed from the sugar part of the nucleoside); Siloxane backbones; Sulfide, sulfoxide and sulfone backbones; Formacetyl and thioformacetyl backbones; Methylene formacetyl and thioformacetyl backbones; Backbones containing alkene; Sulfamate backbones; Methylene imino and methylene hydrazino backbones; Sulfonate and sulfonamide backbones; Amide backbones; and others with mixed N, O, S and CH 2 component parts.
- both the sugar and the internucleoside linkage i.e. modified the backbone of natural nucleotide units.
- the bases are usually retained for hybridization with a suitable target nucleic acid.
- PNA peptide nucleic acid
- nucleobases are preserved and directly or indirectly bound to the nitrogen atoms of the amide part of the backbone.
- the present invention relates to oligonucleotides with phosphothioate backbones and furthermore oligonucleosides with heteroatom backbones, which are based in particular on structural units, such as -CH 2 -NH-O-CH 2 -, -CH 2 - N (CH 3 ) -O-CH 2 - [known as methylene methylimino or MMI backbone for short], -CH 2 -O- N (CH 3 ) -CH 2 -, -CH 2 -N (CH 3 ) -N (CH 3 ) - CH 2 - or -ON (CH 3 ) -CH 2 -CH 2 -.
- structural units such as -CH 2 -NH-O-CH 2 -, -CH 2 - N (CH 3 ) -O-CH 2 - [known as methylene methylimino or MMI backbone for short], -CH 2 -O- N (CH 3 ) -CH 2 -
- Modified oligonucleotides can also contain one or more substituted sugar groups.
- the 2'-position can be substituted with OH, F, O-, S- or N-alkyl, OS- or N-alkenyl, O-, S- or N-alkynyl, or O-alkyl-O-alkyl, wherein alkyl, alkenyl and alkynyl are preferably substituted or unsubstituted C 1 -C 4 -alkyl or C 2 -C 10 -alkenyl or alkynyl.
- substituents such as O [(CH 2 ) nO] mCH 3 , O (CH 2 ) n OCH 3 , O (CH 2 ) n NH 2 , O (CH 2 ) n CH 3 , O (CH 2 ) n NH 2 and O (CH 2 ) n ON [(CH 2 ) n CH 3 )] 2 , where n and m are integers from 1 to 10.
- Preferred modifications include an alkoxy-alkoxy group, eg Z-methoxyethoxy (2'-O-CH 2 CH 2 OCH 3 , also known as 2'-O- (2-methoxymethyl) or Z-MOE).
- Another preferred modification includes 2'-dimethylaminooxyethoxy, ie an O (CH 2 ) 2 ON (CH 3 ) 2 group, also known as Z-DMAOE.
- Oligonucleotides according to the invention can also have sugar mimetics, such as cyclobutyl groups, instead of the pentofuranosyl sugar.
- oligonucleotides include that one or more groups or conjugates are linked to the oligonucleotide, which increase the activity, cellular distribution or cellular uptake of the oligonucleotides.
- groups include above all polyglycols, in particular polyalkylene glycols, preferably polyethylene glycols, peptides and especially lipophilic residues, such as fatty acid residues with preferably 8 to 32 carbon atoms, which can be saturated or mono- or polyunsaturated, cholesterol, tocopherols, in particular ⁇ -tocopherol and hioervon especially the naturally occurring D-enantiomer, or steroids, and derivatives thereof, in particular cholic acid, thioethers, for example Hexyl-S-tritylthiol, thiocholesterol, aliphatic chains, e.g.
- Dodecanediol or undecyl residues phospholipids, e.g. Dihexyldecyl-rac-glycerol or triethylammonium-1, 2-die-O-hexadecyl-rac-glycero-3-H-phosphonate, polyamine chains, adamantane acetic acid, palmityl groups, or octadecylamine or hexylaminocarbonyloxicholesterol groups.
- the conjugates include, for example, nanoparticles, which are expediently positively charged. Diameters from 100 to 500 nm can be used. Polymers are particularly used in this context. Particles based on polystyrene or polyacrylate should be mentioned in particular.
- the modification with lipophilic residues increases the bioavailability because of the half-life extended by orders of magnitude compared to the attack by nucleases. Similar effects are also achieved with certain hydrophilic residues such as polyethylene glycols, especially in the 3'-position. If the oligonucleotides according to the invention are conjugated to positively charged nanoparticles, the Stability to attack by nucleases was increased both in the case of unmodified, terminally modified phosphorothioate linkages and also modified oligonucleotides, and an excellent uptake in tumor cells was observed.
- oligonucleotides which are terminally modified.
- further modifications of oligonucleotides according to the invention can relate to individual nucleosides, it being possible for several nucleosides to be modified differently or uniformly. Mixtures of differently modified oligonucleotides can also be used according to the invention, in particular with regard to the use according to the invention.
- the compounds according to the invention can be prepared in a manner known per se.
- Known solid phase synthesis systems are used in particular. Suitable devices are commercially available, for example from Applied Biosystems (Foster City, California). Accordingly, the compounds are synthesized in vitro.
- esters Suitable are pharmaceutically acceptable salts, esters, salts of the esters or any other compounds which, after administration to an animal, in particular humans, are able, directly or indirectly, to supply the biologically active metabolite or a part thereof.
- Prodrugs can also be used. This is an inactive form of the active ingredient that is converted into an active form in vivo.
- Prodrug versions of oligonucleotides can be provided, for example, as S- (acetyl-2-thioethyl) phosphate derivatives.
- the pharmaceutically acceptable base addition salts include salts with metals or amines, such as alkali and alkaline earth metals or organic amines, in particular cations such as sodium, potassium, ammonium, magnesium and calcium or polyamines such as spermine and spermidine.
- the pharmaceutically acceptable acid addition salts include salts with inorganic bases, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, and with organic acids, for example acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, malic acid, malic acid, malic acid, malic acid Benzoic acid, tannic acid, palmitic acid, alginic acid, Polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalactoronic acid and the like.
- organic acids for example acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, malic acid
- oligonucleotides with the following sequences:
- sequence SEQ ID NO: 1 exemplifies an antisense oligonucleotide for suppressing the gene expression of the mutant p53 protein
- sequence SEQ ID NO: 2 is an example of a sequence selected from a randomized oilgonucleotide library. Further sequences can be selected from antisense sequences or randomized oilgonucleotide libraries in the context of the invention and modified if necessary, in particular by using one or more of the following selection criteria:
- Another object of the present invention is the use of a compound according to the invention for inhibiting the proliferation of tumor cells.
- This use also includes a method for inhibiting the proliferation of tumor cells, wherein at least one oligonucleotide according to the invention is allowed to act on tumor cells.
- this method can be an in vitro, ex vivo or in vivo method.
- Corresponding systems for example in the form of cells or Tissues can be provided in culture in a manner known per se in vitro or ex vivo.
- An in vivo application usually involves the administration of the oligonucleotide to the individual concerned.
- Such tumor cell systems can be provided in a conventional manner by the person skilled in the art.
- techniques are known for causing organisms and cells to degenerate accordingly, for example using recombinant techniques. It is also common to cultivate organisms, cells or tissues in a suitable manner and in particular to assess the proliferation qualitatively and, if desired, quantitatively using suitable assays.
- oligonucleotides according to the invention can also be accomplished with common specialist knowledge.
- the individual is administered a certain amount of at least one oligonucleotide according to the invention, generally formulated in accordance with pharmaceutical or veterinary practice.
- the present invention also relates to agents and in particular pharmaceutical agents which comprise at least one oligonucleotide according to the invention and, if desired, suitable auxiliaries which in particular form a pharmaceutically acceptable formulation basis.
- suitable auxiliaries which in particular form a pharmaceutically acceptable formulation basis.
- oligonucleotides according to the invention can serve, for example, scientific purposes in the context of these uses and methods. Above all, the compounds according to the invention can be used for therapeutic purposes.
- treatment means preventive or prophylactic, or at least delay, or alleviate or remedy acute or chronic, i.e. in particular, reduce and, if necessary, suppress the proliferation of the tumor, thereby reducing the extent of the tumor and reducing the risk or incidence for metastases derived from the primary tumor.
- the present invention therefore also relates to the use of at least one compound according to the invention for the treatment of tumors.
- This use also includes a method in which an effective amount of at least one compound according to the invention is administered to an individual to be treated, in particular a human being and also a farm animal or pet. Administration is usually carried out once or several times a day, if appropriate together or alternating with other active substances or preparations containing active substances.
- the therapy can include the use of further treatment measures, for example chemotherapy by administration of cytostatics or radiation therapy.
- pancreatic tumors there are particular advantages in the treatment of pancreatic tumors, particularly in humans.
- Panc-Tu-I, Pan-Tu-Il, A818-4 and HPAF cell lines were primarily used as human pancreatic tumor cells.
- the uptake of the modified ODN by the cells was determined using confocal laser microscopy.
- pancreas After laparotomy under anesthesia, animals were injected with 1 ⁇ 10 6 PancTu-1 cells into the pancreas.
- One group was treated subcutaneously (implanted continuous pumps (ALZET ⁇ pumps), the other group was treated with ODN intraperitoneally once a day in one
- mice were sacrificed after 14 and 21 days, respectively.
- pancreatic tumors were weighed and measured to calculate the volume using the formula ⁇ / 6x height x length x width. Liver, lungs, omentum and spleen were removed to be typical
- Figure 1a shows the size and Figure 1b the weight growth of 2 treatment groups with the ODN 5 ocopheryl-TGC TCC CCC CTG GCT-3 ' -PEG1500 as phosphorothioates.
- the size and weight growth is significantly reduced compared to the control group.
- the volume of the tumor decreased by 64% after intraperitoneal injection. Treatment with the subcutaneous continuous pump appears even cheaper.
- the volume of the tumors decreased by 70% after 21 days.
- the histological and histochemical examinations of the organs show no striking findings.
- Figure 2 shows the dose dependence of the effect.
- Pancreatic tumors The volume and weight of the tumor has also decreased by approximately 2/3. This shows that not only does the growth of human pancreatic tumors stop in vivo, but that a marked reduction in the tumor is achieved within 2-3 weeks. This is also of outstanding importance insofar as the PancTuI pancreatic adenocarcinoma cell line used in vivo is a very apoptosis-resistant tumor cell line that is completely inert to numerous other treatment strategies (e.g. triggering programmed cell death through Fas / CD95 activation, TRAIL or chemotherapy drugs) ,
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10048091A DE10048091A1 (en) | 2000-09-28 | 2000-09-28 | Use of chemically modified oligodeoxyribonucleotides to suppress the proliferation of human pancreatic tumors |
DE10048091 | 2000-09-28 | ||
PCT/EP2001/011258 WO2002026754A2 (en) | 2000-09-28 | 2001-09-28 | Oligonucleotides, agents containing these oligonucleotides, and the use thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1326878A2 true EP1326878A2 (en) | 2003-07-16 |
Family
ID=7657971
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01985701A Withdrawn EP1326878A2 (en) | 2000-09-28 | 2001-09-28 | Oligonucleotides, agents containing these oligonucleotides, and the use thereof |
Country Status (5)
Country | Link |
---|---|
US (1) | US7608705B2 (en) |
EP (1) | EP1326878A2 (en) |
AU (1) | AU2002215911A1 (en) |
DE (1) | DE10048091A1 (en) |
WO (1) | WO2002026754A2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10048091A1 (en) | 2000-09-28 | 2002-04-25 | Ernst Bayer | Use of chemically modified oligodeoxyribonucleotides to suppress the proliferation of human pancreatic tumors |
DE10346721A1 (en) * | 2003-10-08 | 2005-05-04 | Holger Kalthoff | New oligonucleotides, useful for treating cancer, especially of the pancreas, are not species specific but induce apoptosis or inhibit proliferation |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS638396A (en) * | 1986-06-30 | 1988-01-14 | Wakunaga Pharmaceut Co Ltd | Poly-labeled oligonucleotide derivative |
US6395492B1 (en) * | 1990-01-11 | 2002-05-28 | Isis Pharmaceuticals, Inc. | Derivatized oligonucleotides having improved uptake and other properties |
US5245022A (en) * | 1990-08-03 | 1993-09-14 | Sterling Drug, Inc. | Exonuclease resistant terminally substituted oligonucleotides |
JP2823959B2 (en) * | 1991-10-24 | 1998-11-11 | アイシス・ファーマシューティカルス・インコーポレーテッド | Derivatized oligonucleotides with improved uptake and other properties |
US6033909A (en) * | 1992-01-22 | 2000-03-07 | Hoechst Aktiengesellschaft | Oligonucleotide analogs, their preparation and use |
US5552390A (en) * | 1993-12-09 | 1996-09-03 | The Board Of Regents Of The University Of Nebraska | Phosphorothioate inhibitors of metastatic breast cancer |
WO1997039028A1 (en) * | 1996-04-12 | 1997-10-23 | American National Red Cross | Mutant plasminogen activator-inhibitor type 1 (pai-1) and uses thereof |
EP0856579A1 (en) * | 1997-01-31 | 1998-08-05 | BIOGNOSTIK GESELLSCHAFT FÜR BIOMOLEKULARE DIAGNOSTIK mbH | An antisense oligonucleotide preparation method |
US6100090A (en) * | 1999-06-25 | 2000-08-08 | Isis Pharmaceuticals Inc. | Antisense inhibition of PI3K p85 expression |
ATE332969T1 (en) * | 1998-10-26 | 2006-08-15 | Avi Biopharma Inc | MORPHOLINE-BASED P53 ANTISENSE OLIGONUCLEOTIDE AND USES THEREOF |
US6107091A (en) * | 1998-12-03 | 2000-08-22 | Isis Pharmaceuticals Inc. | Antisense inhibition of G-alpha-16 expression |
US6037142A (en) * | 1999-02-23 | 2000-03-14 | Isis Pharmaceuticals Inc. | Antisense inhibition of SMAD2 expression |
US6013788A (en) * | 1999-04-09 | 2000-01-11 | Isis Pharmaceuticals Inc. | Antisense modulation of Smad3 expression |
US6124272A (en) * | 1999-04-09 | 2000-09-26 | Isis Pharmaceutical Inc. | Antisense modulation of PDK-1 expression |
US6080546A (en) * | 1999-07-23 | 2000-06-27 | Isis Pharmaceuticals Inc. | Antisense modulation of MEKK5 expression |
CA2392094A1 (en) * | 1999-11-18 | 2001-05-25 | Genesense Technologies Inc. | Antisense oligonucleotide sequences derived from groel and groes as inhibitors of microorganisms |
EP1268856A2 (en) * | 2000-04-07 | 2003-01-02 | Epigenomics AG | Detection of single nucleotide polymorphisms (snp's) and cytosine-methylations |
DE10048091A1 (en) | 2000-09-28 | 2002-04-25 | Ernst Bayer | Use of chemically modified oligodeoxyribonucleotides to suppress the proliferation of human pancreatic tumors |
-
2000
- 2000-09-28 DE DE10048091A patent/DE10048091A1/en not_active Ceased
-
2001
- 2001-09-28 US US10/381,869 patent/US7608705B2/en not_active Expired - Fee Related
- 2001-09-28 AU AU2002215911A patent/AU2002215911A1/en not_active Abandoned
- 2001-09-28 EP EP01985701A patent/EP1326878A2/en not_active Withdrawn
- 2001-09-28 WO PCT/EP2001/011258 patent/WO2002026754A2/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0226754A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU2002215911A1 (en) | 2002-04-08 |
WO2002026754A2 (en) | 2002-04-04 |
DE10048091A1 (en) | 2002-04-25 |
US7608705B2 (en) | 2009-10-27 |
WO2002026754A9 (en) | 2003-05-15 |
WO2002026754A3 (en) | 2002-12-05 |
US20050019761A1 (en) | 2005-01-27 |
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