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WO1991003260A1 - Oligonucleotides non codants pour le proto-oncogene c-abl - Google Patents

Oligonucleotides non codants pour le proto-oncogene c-abl Download PDF

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Publication number
WO1991003260A1
WO1991003260A1 PCT/US1990/004961 US9004961W WO9103260A1 WO 1991003260 A1 WO1991003260 A1 WO 1991003260A1 US 9004961 W US9004961 W US 9004961W WO 9103260 A1 WO9103260 A1 WO 9103260A1
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abl
σlaim
aσσording
gca gat
tcc agg
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PCT/US1990/004961
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English (en)
Inventor
Bruno Calabretta
Alan M. Gewirtz
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Temple University Of The Commonwealth System Of Higher Education
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Publication of WO1991003260A1 publication Critical patent/WO1991003260A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—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
    • C12N15/1135—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 against oncogenes or tumor suppressor genes
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/82—Translation products from oncogenes
    • 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)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to antisense oligonucleotides to proto-oncogenes, in particular to antisense oligonu- cleotides to the c-abl gene, and the use of such oligonu ⁇ cleotides to selectively inhibit proliferation of myeloid cells.
  • CML chronic myelogenous leukemia
  • the structural alterations in leukocyte DNA are caused by the translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22 (t(9; 22)(q34; qll)) , and the resulting formation of a bcr-abl hybrid gene.
  • the translocation results in a truncated chromosome 22, the so-called "Philadelphia chromosome".
  • the fused bcr-abl gene is transcribed into a long primary transcript, which is spliced into a chimeric mRNA.
  • the 8 kilobase (kb) chimeric mRNA is translated into a 210 kd bcr-abl protein unique to CML.
  • the most characteristic clinical feature of the chronic phase of CML is an increase of mature and imma ⁇ ture myeloid elements in bone marrow and peripheral blood. Terminal differentiation of cells is maintained, resulting in profoundly elevated counts of circulating mature granulocytes. Kinetic studies indicate that these abnormal cells do not proliferate or mature faster than their normal counterparts. Rather, the basic defect underlying the exuberant granulopoiesis in CML appears to be an expansion of the myeloid progenitor cell pool in bone marrow and peripheral blood. Galbraith et al., Br. J. Haematol. 22, 135 (1972). Although hematopoiesis in the chronic phase of CML is altered, it retains some normal features.
  • the c-abl proto-oncogene resides on the long arm of chromosome 9 (band q34) . Cloning of the c-abl gene has revealed that it spans at least 230 kb, and contains at least 11 exons. Two alternative first exons exist, name ⁇ ly exon la and exon lb. Exon la is 19 kb proximal to exon 2. Exon lb is more than 200 kb proximal to exon 2. As a result of this configuration, at least two major c- abl messages are transcribed. Each of exons la and lb are preceded by a transcriptional promotor.
  • the two distinct c-abl mRNAs differing in their 5' regions have been identified. Shtivelman et al.. Cell 47, 277 (1986); Bernards et al., Mol. Cell. Biol. 7, 3231 (1987) .
  • the 6-kb transcript consists of exons la through 11.
  • the 7-kb transcript begins with exon lb, skips the 200 kb distance to exon 2, omits exon la, and joins to exons 2 through 11.
  • both c-abl messages share a common set of 3 • exons, starting from the c-abl exon 2. Consequently, the messages code for two proteins that share most of their amino acid sequence, except for the N-termini. Since the coding begins with the first exon, exonic selection will determine the protein product.
  • c-abl antisense RNA probes hybridizable with c- abl mRNA have been used to detect c-abl transcription, Klimfinger et al., Virchos Archiv. B-Cell Phathol. 54, 256-259 (1988), Griel et al.. Lab. Invest. 60, 574-582 (1989) , c-abl antisense has not heretofore been recog ⁇ nized as being useful for selectively inhibiting myeloid cell proliferation.
  • Antisense oligonucleotides and pharmaceutical com ⁇ positions thereof with pharmaceutical carriers are pro ⁇ vided.
  • Each oligonucleotide has a nucleotide sequence complementary to at least a portion of the mRNA tran- script of the human c-abl gene.
  • the oligonucleotide is hybridizable to the mRNA transcript.
  • the oligonucleotide is at least a 15-mer oligodeoxynucleo- tide, that is, an oligomer containing at least 15 deoxy- nucleotide residues.
  • the oligodeoxy- nucleotide is a 15- to 21-mer.
  • oligo ⁇ nucleotides having a sequence complementary to any region of the c-abl gene find utility in the present invention
  • oligodeoxynucleotides complementary to a portion of the c-abl mRNA transcript beginning with the second codon from the 5* end of the transcript are particularly pre ⁇ ferred.
  • oligo ⁇ nucleotide includes both oligomers of ribonucleotide i.e., oligoribonucleotides, and oligomers of deoxyribo- nucleotide i.e., oligodeoxyribonucleotides (also referred to herein as "oligodeoxynucleotides”) .
  • oligonucleotide also includes oligomers which may be large enough to be termed “polynucleotides”.
  • oligonucleotide and “oligodeoxynucleo- tide” include not only oligomers and polymers of the biologically significant nucleotides, i.e. nucleotides of adenine ("A”), deoxyadenine ("dA”) , guanine (“G”) , deoxy- guanine (“dG”) , cytosine ("C”) , deoxycytosine (“dC”) , thymine (“T”) and uracil (“U”) , but also oligomers and polymers hybridizable to the c-abl mRNA transcript which may contain other nucleotides.
  • nucleotides i.e. nucleotides of adenine (“A”), deoxyadenine (“dA”) , guanine (“G”) , deoxy- guanine (“dG”) , cytosine (“C”) , deoxycytosine (“dC”) , thymine (“T”) and urac
  • oligonucleotide and “oligodeoxynucleotide” include oligomers and polymers wherein one or more purine or pyrimidine moieties, sugar moieties or internucleotide linkages is chemically modified.
  • c-abl mRNA transcript means either or both of the presently known mRNA transcripts of the human c-abl gene, or any further transcripts which may be elucidated.
  • the invention provides a method for inhibiting proliferation of myeloid cells comprising administering to an individual or cells harvested from the individual, c-abl antisense oligonucleotide.
  • c-abl gene plays a critical role in regulating normal human hematopoiesis, and that its function is lineage-specific.
  • c-abl antisense oligonucleotides that is, oligonucleotides complementary to and hybridizable with the mRNA transcript of the human c-abl gene, effects two major populations of hematopoietic cells differently.
  • c-abl antisense oligonucleotides inhibit myeloid, but not erythroid cells. This differential sensitivity makes possible the use of c-abl antisense to treat dis- orders such as CML which are characterized by the expan ⁇ sion of the myeloid progenitor cell population.
  • the putative partial DNA sequence complementary to the mRNA transcript of the human c-abl gene has been reported in Shtivelman et al.. Cell 47, 277-284 (1986), the entire disclosure of which is incorporated herein by reference.
  • the nucleotide sequence and predicted amino acid sequence of the open reading from the initiation codon are set forth in Figure IB of Shtivelman et al.
  • the open reading frame spans the region between nucleo- tides 148 and 3537 of the cDNA and codes for a protein of 1130 amino acids.
  • the antisense oligonucleotides of the invention may be synthesized by any of the known chemical oligonucleo ⁇ tide synthesis methods. Such methods are generally described, for example, in Winnacker, From Genes to Clones: Introduction to Gene Technology, VCH Verlags- gesellschaft mbH (H. Ibelgaufts trans. 1987) .
  • the antisense oligonucleotides are most advantag ⁇ eously prepared by utilizing any of the commercially available, automated nucleic acid synthesizers, for ex ⁇ ample, the Applied Biosystems 380B DNA Synthesizer, which utilizes y9-cyanoethyl phosphoramidite chemistry.
  • antisense oligonucleotides hybridizable with any portion of the mRNA transcript may be prepared by the oligonucle- otide synthesis methods known to those skilled in the art.
  • oligonucleotide While any length oligonucleotide may be utilized in the practice of the invention, sequences shorter than 15 bases may be less specific in hybridizing to the target c-abl mRNA, and may be more easily destroyed by enzymatic digestion. Hence, oligonucleotides having 15 or more nucleotides are preferred. Sequences longer than 18 to 21 nucleotides may be somewhat less effective in inhibit- ing c-abl translation because of decreased uptake by the target cell. Thus, oligomers of 15-21 nucleotides are most preferred in the practice of the present invention, particularly oligomers of 15-18 nucleotides.
  • Oligonucleotides complementary to and hybridizable with any portion of the c-abl mRNA transcript are, in principle, effective for inhibiting translation of the transcript, and capable of inducing the effects herein described. It is believed that translation is most effectively inhibited by blocking the mRNA at a site at or near the initiation codon. Thus, oligonucleotides complementary to the 5'-terminal region of the c-abl mRNA transcript are preferred. The oligonucleotide is prefer ⁇ ably directed to a site at or near the initiation codon for protein synthesis.
  • Oligonucleotides complementary to the c-abl mRNA may be thus advantageously employed. Since there are at least two mRNA c-abl transcripts, a 6.0 kb transcript containing exon la, and a 7.0 kb transcript containing alternative exon lb, two sets of preferred 15- 21 nucleotide oligomers are possible.
  • oligonucleotides complimentary to the 5'- terminal regions of either the 6.0 kb or 7.0 kb trans ⁇ cripts translation may be effectively blocked by oligo ⁇ nucleotides complimentary to common sequences shared by both transcripts.
  • oligonucleotides complimentary to and hybridizable with any portion of the transcript containing the common exon 2 may be utilized.
  • 15- through 21-mer oligodeoxy- nucleotides complimentary to a region of exon 2 beginning with the second codon thereof is a preferred embodiment of the invention: 5'-TGC TAC TGG CCG CTG AAG GGC-3'
  • Oligonucleotides hybridizable to the c-abl mRNA transcript finding utility according to the present invention include not only native oligomers of the biologically significant nucleotides, i.e..
  • oligonucleotide species which have been modified for improved stability and/or lipid solubility.
  • enhanced lipid solubility and/or resistance to nuclease digestion results by substituting a methyl group or sulfur atom for a phosphate oxygen in the internucleotide phosphodiester linkage.
  • the phosphorothioates in particular, are stable to nuclease cleavage and soluble in lipid. They may be synthesized by known automatic synthesis methods.
  • the antisense oligonucleotides of the invention inhibit human myelopoiesis. However, they do not affect erythropoiesis. This pharmaceutically significant dif ⁇ ferential sensitivity makes the instant oligonucleotides very useful in treating myeloproliterative disorders.
  • Myeloproliterative disorders refer to certain diseases in which the marrow and sometimes hematopoietic stem cells in extramedullary sites proliferate more or less en masse.
  • the proliferation is self-perpetuating, resembling neoplastic disease.
  • Such disorders include for example, CML, polycythemia vera, myelofibrosis with myeloid metaplasia, and essential (idiopathic) throm- bocythemia.
  • CML in particular, is characterized by abnormal proliferation of immature granulocytes - neutrophils, eosinophils, and basophils - in the blood, the bone marrow, the spleen, the liver, and sometimes other tissues.
  • the essential feature is accumulation of granulocytic precursors in the blood, bone marrow, and spleen.
  • the patient who presents symptoms will charac ⁇ teristically have more than 20,000 white blood cells per ⁇ l, and the count may exceed 400,000.
  • Some 60 to 80 percent of CML patients will develop "blast crisis", the terminal stage of the disease during which immature blast cells rapidly proliferate, leading to patient death.
  • Antisense oligomers to the c-abl proto-oncogene are use ⁇ ful for controlling or arresting such myeloproliterative disorders, in particular in arresting the abnormal myelo- poiesis which characterizes CML.
  • the sparing of erythroid lineage cells is not without sig ⁇ nificance, since individuals afflicted with myelopro- 1iterative disorders in many cases suffer from anemia of varying degree, due to the crowding out of erythroid cells in response to myeloid expansion.
  • anemia results from prolonged chemotherapeutic treatment of myeloproliterative disorders with conventional chemical agents.
  • the anemia is typically treated by transfusion therapy, which is expensive and not without possible short and long term side effects.
  • Treatment with c-abl antisense oligonucleotide permits the substantial reduc ⁇ tion of myeloid cell numbers, without sacrificing erthy- roid cells and aggravating the anemic condition.
  • a myeloid cell proliferation inhibiting-amount of the antisense oligonucleotides may be combined with a pharmaceutical carrier, such as a suitable liquid vehicle or excipient and an optional auxiliary additive or additives.
  • a suitable liquid vehicle or excipient such as distilled water, physiological saline, aqueous solution of dextrose, and the like.
  • the c-abl mRNA antisense oligonucleotides are preferably administered intravenously.
  • oligoribonucleotides While inhibition of c-abl mRNA translation is pos ⁇ sible utilizing either antisense oligoribonucleotides or oligodeoxyribonucleotides, oligoribonucleotides are more susceptible to enzymatic attack by ribonucleases than deoxyribonucleotides. Hence, oligodeoxyribonucleotides are preferred in the practice of the present invention.
  • the antisense oligonucleotides may be adminis ⁇ tered by a variety of specialized oligonucleotide deliv ⁇ ery techniques.
  • oligonucleotides have been successfully encapsulated in unilameller liposomes.
  • Reconstituted Sendai virus envelopes have been success- fully used to deliver RNA and DNA to cells. Arad et al., Biochem. Biophy. Acta. 859, 88-94 (1986).
  • the c-abl antisense oligonucleotides may be admin ⁇ istered to an individual suffering from a myeloprolifera- tive disorder in an amount sufficient to inhibit prolif- eration of myeloid lineage cells. Generally, it will be desirable to administer sufficient oligonucleotide to result in substantial reduction of the myeloid cell population without significantly affecting erythroid cell numbers.
  • the actual dosage administered may take into account the size and weight of the patient, whether the nature of the treatment is prophylactic or therapeutic in nature, the age, weight, health and sex of the patient, the route of administration, and other factors.
  • the daily dosage may range from about 0.1 mg to 1 g oligonuc- leotide per day, preferably from about 10 to about 1,000 mg per day. Greater or lesser amounts of oligonucleotide may be administered, as required. Based upon the experi ⁇ ments hereinafter described, a dosage sufficient to provide a plasma antisense oligonucleotide concentration of about 14 ⁇ l may be utilized. Other dosages will be apparent to those skilled in the art by routine experi ⁇ mentation.
  • c-abl 4 the c-abl antisense 18-mer, 5'-CTT CAG GCA GAT CTC CAA-3' , which is complementary to the 6.0 kb c-abl mRNA transcript beginning with the second codon (hereinafter "c-abl 4") ;
  • c-abl 6 the c-abl antisense 18-mer, 5'-TAC TGG CCG CTG AAG GGC-3' , which is complementary to 18 nucleo ⁇ tides of the second exon of c-abl (codons 2 through 7) , which is common to both c-abl mRNAs (hereinafter "c-abl 6") ;
  • the cells (2.5 x 10* cells) were plated in 1 ml of IMDM supplemented with 30% fetal bovine serum, 5 x 10 "" ⁇ jS-2-mercaptoethanol and 0.9% methylcellulose and cultured in the presence of optimum concentration of the growth factors listed below.
  • Each growth factor is specific for the indicated cell subset:
  • CFU-E Colony forming unit-erythroid cells
  • rh Epo 3 ⁇ /ml recombinant erythropoietin
  • BFU- E Burst-forming unit-erythroid cells
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • IL-3 interleukin 3
  • CFU-GM Colony forming unit-granulocyte-macro- phage
  • CFU- G Colony forming unit-granulocytes
  • G-CSF granulocyte-colony stimulating factor
  • CFU-E and CFU-G colonies were scored after seven and nine days of growth, respectively.
  • CFU-GM and BFU-E colonies were scored after fourteen days of culture.
  • exposure of bone marrow mononu ⁇ lear cells to c-abl antisense oligomers did not effect erythroid colony formation deriving from BFU-E and CFU-G progenitors, but markedly inhibited (10% to 20% of residual growth in comparison to controls) myeloid colony formation deriving from CFU-G and CFU-GM progenitors.
  • the residual myeloid colonies were much smaller than those formed in the presence of c-abl sense oligo ⁇ mers.
  • a bcr antisens oligomer did not have any effect on colony number or colony size.
  • Peripheral blood progenitors are antigeni ⁇ ally distinct from, and less differentiated than, progenitors found in the bone marrow. Ferrero et al., Proc. Natl. Sci. USA 80, 4114 (1983) . CFU-GM ⁇ olonies were grown in the presen ⁇ e of re ⁇ ombinant GM-CSF and IL-3 from adherent- and T- ⁇ ell depleted peripheral blood mononu ⁇ lear ⁇ ells after sixteen days of ⁇ ulture.
  • CFU-GM ⁇ olonies formed from peripheral blood progenitors in the presen ⁇ e of the ⁇ -abl antisense oligomer were indistinguishable from those derived from similarly treated bone marrow progenitors, and were mu ⁇ h smaller than progenitors arising in the presen ⁇ e of ⁇ -abl sense oligomer.
  • the number of ⁇ olonies formed was inhibited essentially to the same degree (75% to 85%) as that observed for bone marrow progenitors. Growth of erythroid progenitors was inhibited slightly more (20% to 25%) than we had observed for bone marrow erythroid progenitors (10% to 20%) .
  • C-abl antisense oligomer ⁇ omplementary to the common se ⁇ ond ⁇ -abl exon was also found to inhibit the expression of the hybrid bcr-abl product in K562 cells, a CML cell line ⁇ ontaining multiple ⁇ opies of the hybrid b ⁇ r- abl gene.
  • the K562 line has been isolated from a Philadel ⁇ phia ⁇ hromosome positive patient with CML in blast ⁇ risis.
  • the ⁇ -abl se ⁇ ond exon is spli ⁇ ed to b ⁇ r exons "2" and "3", Shtivelman el al.. Cell 47, 277 (1986) .

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Abstract

On prévoit des oligonucléotides qui possèdent une séquence nucléotidique complémentaire à au moins une portion de la transcription mARN du gène c-abl humain. Ces oligonucléotides ''non codants'' sont hybridables à la transcription mARN c-abl. Ces oligonucléotides sont utiles à l'inhibition de la prolifération des cellules myéloïdes, notamment dans le cas des troubles myéloprolifératifs tels que la leucémie myélogène chronique.
PCT/US1990/004961 1989-09-01 1990-08-29 Oligonucleotides non codants pour le proto-oncogene c-abl WO1991003260A1 (fr)

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US402,383 1989-09-01

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EP (1) EP0489846A4 (fr)
JP (1) JPH05500217A (fr)
AU (1) AU646643B2 (fr)
CA (1) CA2065294A1 (fr)
WO (1) WO1991003260A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993008845A1 (fr) * 1991-11-08 1993-05-13 Massachusetts Institute Of Technology Traitement par application localisee d'oligonucleotides
WO1994010302A1 (fr) * 1992-10-29 1994-05-11 Boehringer Mannheim Gmbh Vecteur amplifiable agissant a l'encontre de la replication du vih
WO1995002057A1 (fr) * 1993-07-09 1995-01-19 The Institute Of Cancer Research Tyrosine kinase et ses ligands
EP0458829B1 (fr) * 1989-02-15 1996-09-25 Board Of Regents, The University Of Texas System Procedes et compositions de traitement du cancer a l'aide d'oligonucleotides
WO1997008184A1 (fr) * 1995-08-30 1997-03-06 Arch Development Corporation Procedes et compositions comprenant des agents alterant l'adn et des inhibiteurs ou des activateurs de la tyrosine kinase
US6080851A (en) * 1992-12-04 2000-06-27 American Home Products Corporation Ribozymes with linked anchor sequences
WO2001048190A3 (fr) * 1999-12-23 2002-05-10 Exiqon As Utilisations therapeutiques d'oligonucleotides a lna modifie

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4689320A (en) * 1983-10-17 1987-08-25 Akira Kaji Method for inhibiting propagation of virus and anti-viral agent
US4806463A (en) * 1986-05-23 1989-02-21 Worcester Foundation For Experimental Biology Inhibition of HTLV-III by exogenous oligonucleotides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3744785A1 (de) * 1987-12-11 1989-08-17 Theurer Karl Eugen Verwendung von ruecklaeufigen spiegelbildlichen anti-sense-nucleinsaeuren gegen krebserkrankungen

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4689320A (en) * 1983-10-17 1987-08-25 Akira Kaji Method for inhibiting propagation of virus and anti-viral agent
US4806463A (en) * 1986-05-23 1989-02-21 Worcester Foundation For Experimental Biology Inhibition of HTLV-III by exogenous oligonucleotides

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Cell, Volume 47, Issued 24 October 1986, SHTIVELMAN et al., "Alternative Splicing of RNAs Transcribed from the Human Abl Gene and from the bcr-abl Fused Gene", see pages 277-284, especially page 277. *
Proc. Natl. Acad. Sci., Volume 85, issued February 1988 (Washington, D.C.) WICKSTROM et al., "Human promyelocytic leukemia HL-60 cell proliferation and C-Myc protein expression are inhibited by an antisense pentadecadeoxynucleotide target against C-Mvc mRNA", see pp. 1028-1032. *
See also references of EP0489846A4 *
Virchows Archiv beta Cell Pathology, Volume 54, Issued 1988, KLIMPFINGER et al., "Oncogene expression in a medullary thyroid carcinoma" see pp. 256-259. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0458829B1 (fr) * 1989-02-15 1996-09-25 Board Of Regents, The University Of Texas System Procedes et compositions de traitement du cancer a l'aide d'oligonucleotides
WO1993008845A1 (fr) * 1991-11-08 1993-05-13 Massachusetts Institute Of Technology Traitement par application localisee d'oligonucleotides
WO1994010302A1 (fr) * 1992-10-29 1994-05-11 Boehringer Mannheim Gmbh Vecteur amplifiable agissant a l'encontre de la replication du vih
US6080851A (en) * 1992-12-04 2000-06-27 American Home Products Corporation Ribozymes with linked anchor sequences
WO1995002057A1 (fr) * 1993-07-09 1995-01-19 The Institute Of Cancer Research Tyrosine kinase et ses ligands
WO1997008184A1 (fr) * 1995-08-30 1997-03-06 Arch Development Corporation Procedes et compositions comprenant des agents alterant l'adn et des inhibiteurs ou des activateurs de la tyrosine kinase
WO2001048190A3 (fr) * 1999-12-23 2002-05-10 Exiqon As Utilisations therapeutiques d'oligonucleotides a lna modifie

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AU646643B2 (en) 1994-03-03
AU6410790A (en) 1991-04-08
CA2065294A1 (fr) 1991-03-02
EP0489846A1 (fr) 1992-06-17
JPH05500217A (ja) 1993-01-21

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