WO1996037605A2 - OLIGONUCLEOTIDES ANTISENS POUR BLOQUER LA SYNTHESE DU RECEPTEUR DE L'IgE - Google Patents
OLIGONUCLEOTIDES ANTISENS POUR BLOQUER LA SYNTHESE DU RECEPTEUR DE L'IgE Download PDFInfo
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- WO1996037605A2 WO1996037605A2 PCT/FR1996/000785 FR9600785W WO9637605A2 WO 1996037605 A2 WO1996037605 A2 WO 1996037605A2 FR 9600785 W FR9600785 W FR 9600785W WO 9637605 A2 WO9637605 A2 WO 9637605A2
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- Prior art keywords
- oligonucleotide according
- modified
- oligonucleotides
- oligonucleotide
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- 239000000074 antisense oligonucleotide Substances 0.000 title claims abstract description 11
- 238000012230 antisense oligonucleotides Methods 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 9
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Classifications
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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
- C12N15/1138—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 receptors or cell surface proteins
-
- 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
- C12N2310/33—Chemical structure of the base
- C12N2310/337—Chemical structure of the base in alpha-anomeric form
-
- 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
- the present invention relates to antisense oligonucleotides which selectively hybridize with one or more genes necessary to block the synthesis of the IgE receptor, pharmaceutical compositions containing them and their use as IgE inhibitors.
- Hypersensitivity to IgE is at least one of the major components exerting a mediating effect in the manifestation of allergic reactions of early and late type I phases.
- the pathophysiological mechanism can be broken down into the following phases:
- Mast cells and basophils are not the only target cells activated by IgE and involved in hypersensitivity reactions.
- Other effector cells include epithelial, endothelial and other inflammatory cells.
- the hypersensitivity reaction is triggered when IgE, produced in excess by B cells, interacts with specific receptors on effector cells.
- Fc ⁇ R ⁇ receptor a high affinity receptor
- Fc ⁇ Ru receptor a low affinity receptor
- Fc ⁇ Ru receptor a receptor that is expressed by the subpopulations of B and T lymphocytes. Expression of the type I or Fc ⁇ R ⁇ receptor is necessary for triggering the hypersensitivity reaction.
- a therapeutic approach to the treatment of allergic reactions would consist in blocking the synthesis of IgE or the IgE receptor.
- the antisense strategy is a new therapeutic approach aimed at obtaining the selective modulation of gene expression by a highly selective association of a nucleotide chain (oligonucleotides) with its additional sequence on RNA or messenger DNA or pre-messenger and, therefore, inhibit the synthesis of the corresponding protein.
- the oligonucleotides complementary to the transcripts are called "antisense” oligonucleotides.
- the oligonucleotides having the same sequence as the transcripts are called “sense” oligonucleotides. Initially, these compounds were logically intended to inhibit the formation of a gene product by the suppression of the corresponding messenger RNA, via the hydrolysis mechanism catalyzed by RNAse H. Soon, it appeared that the mechanism of action of these antisense oligonucleotides was not that simple.
- These oligonucleotides can interact with a certain number of cellular targets not comprising nucleic acid.
- Oligonucleotides can interact with the gene, to form triple helix structures and inhibit the formation of transcripts. Oligonucleotides can interact with the intron-exon junctions of pre-messenger RNA, thus interfering with the correct splicing of the transcript. Oligonucleotides can hybridize with messenger RNA in the cytoplasm, forming an RNA-DNA complex, which is rapidly degraded by the RNAse H enzyme, or preventing the ribosome complex from slipping onto the messenger RNA and thereby blocking the translation. Oligonucleotides and, more particularly, modified oligonucleotides, can interact with a number of cellular products such as proteins. These interactions can be sequence-specific (for example: transcription factors) or non-sequence-specific (for example: growth factors).
- Oligonucleotides are very often used as a probe, for example for the identification of a strand complementary to the oligonucleotide studied, from an experimental point of view, in pharmacological experiments.
- oligonucleotides have been used, for example, to demonstrate the ⁇ subunit of the IgE receptor (Proceedings of the National Academy of Sciences of USA, vol. 85, No 15, August 1988, pp. 5639-5643). But in this area, no oligonucleotide has been used for therapeutic purposes.
- the invention relates to antisense oligonucleotides which selectively hybridize with one or more genes necessary to block the synthesis of the IgE receptor. - 3 -
- This invention relates more particularly to antisense oligonucleotides which selectively hybridize with a gene or the transcripts for the ⁇ subunits of the high affinity IgE receptor.
- the oligonucleotides preferably comprise from 8 to 35 units. Very preferably, the oligonucleotides comprise from 10 to 25 units.
- oligonucleotide represents an oligonucleotide consisting of bases, phosphodiester bonds and sugars well known to those skilled in the art.
- oligonucleotides also represents oligonucleotides whose backbone has been modified either over the entire length of the oligonucleotide, or in the 5 ′ position and / or in the 3 ′ position.
- oligonucleotides are sensitive to enzymes, the nucleases which cut them into nucleotides; the oligonucleotides become resistant to nucleases by modification, for example, of the chemical nature of the sugar itself or the phosphate-sugar chain: thus, the phosphodiester chain can be replaced, for example, by a phosphorothioate, phosphorodithioate, methylphosphonate chain , phosphoramidate, phosphoethyltriester, butylamidate, piperazidate or morpholidate.
- oligonucleotide modifications can be made along the entire length of the oligonucleotide or at its 5 ′ and / or 3 ′ ends, to make the oligonucleotides more resistant to a biological environment.
- the phosphate bonds between the nucleotides can also be replaced by amide bonds (peptide nucleic acids).
- the transmembrane passage of the oligonucleotide can be promoted by making the latter more hydrophobic: this can be obtained, for example, by attaching hydrophobic substituents such as cholesterol or aromatic groups, or a polymer.
- Modified bases can be incorporated partially or over the entire length of the oligonucleotide.
- oligonucleotide also represents a nucleotide whose backbone is modified according to any of the methods described above or of any other method well known to those skilled in the art.
- the subject of the invention is the oligonucleotides of the sequences SEQ ID No. 1 to SEQ ID No. 6 respectively; the oligonucleotides of the sequences SEQ ID Nos. 4-6 are oligonucleotides in which all the phosphodiester bonds have been modified into phosphorothioate. Their complementary sequences or sense oligonucleotides according to the invention can also be used.
- the invention also relates to antisense oligonucleotides comprising at least one fragment of one of the sequences selected from the sequences SEQ ID No. 1 to SEQ ID No. 6.
- the oligonucleotides of the invention can be synthesized by any of the known methods of chemical synthesis of the oligonucleotides.
- Antisense oligonucleotides are very advantageously prepared using any commercial nucleic acid synthesizer.
- One of these methods for synthesizing oligonucleotides is the beta-cyanoethyl phosphoramidate method described by S. L. Beaucage & his collaborators (Tet. Let. 22 (1981), 1859-1862).
- a subject of the invention is also pharmaceutical compositions containing, as active principle, at least one antisense oligonucleotide according to the invention, mixed with a pharmaceutically acceptable excipient and / or carrier, according to the mode of administration chosen.
- the composition can be administered by topical or systemic or local treatment; it can take the form of a liquid for an injection, liposome, sustained-release formulation or in the form of a gel, ointment for local application or in any other acceptable form depending on the mode of administration chosen.
- the composition used is in the form of a liposome.
- the invention relates to the use of oligonucleotides according to the invention, for the preparation of medicaments for inhibiting the role of IgE.
- the invention relates more particularly to the use of oligonucleotides according to the invention, for the preparation of medicaments for the treatment of allergies or other pathologies in which the IgE receptor is involved.
- RBL 2H3 cell lines (transformed rat mast cells) were cultured in RPMI-1640 medium, in the presence of 10% fetal calf serum (S VF). These cells were seeded at a rate of 5.10 4 / ml on day 0, with or without the oligonucleotides according to the invention, at a concentration of 1 or 10.10 -6 M, in solution or in the form of a liposome. On day 2, the culture medium was renewed and the oligonucleotides were added at the same concentration and in the same form The cells were further cultured for 2 days and isolated on day 4, immunostained using anti-oc subunit antibody of the high affinity IgE receptor of rats and analyzed by FACS.
- S VF fetal calf serum
- RBL 2H3 cells grown under different conditions, were isolated by trypsinization and counted. For each condition, two aliquots of 5.10 5 cells were treated with PBS / 2% fetal calf serum. One of the two aliquots was treated in an antibody-xTanti-subunit ⁇ of mouse (antibody BC4) then with an anti-mouse Ig, labeled with fluorescein isothiocyanate (ITCF); the other aliquot was treated only with the secondary antibody (anti-ITCF Ig) and was used as a negative control. The percentage of fluorescent cells, in each condition, was determined by analysis by cytofluorimetry.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96917549A EP0828827A2 (fr) | 1995-05-26 | 1996-05-24 | OLIGONUCLEOTIDES ANTISENS POUR BLOQUER LA SYNTHESE DU RECEPTEUR DE L'IgE |
AU60082/96A AU6008296A (en) | 1995-05-26 | 1996-05-24 | Anti sense oligonucleotides for blocking ige receptor synthe sis |
US08/952,597 US5892023A (en) | 1995-05-26 | 1996-05-24 | Anti sense oligonucleotides for blocking IgE receptor synthesis |
NO975423A NO975423D0 (no) | 1995-05-26 | 1997-11-25 | Anti-sense oligonukleotider for blokkering av IgE-reseptorsyntese |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9510718.1A GB9510718D0 (en) | 1995-05-26 | 1995-05-26 | Antisense oligonucleotides |
GB9510718.1 | 1995-05-26 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1996037605A2 true WO1996037605A2 (fr) | 1996-11-28 |
WO1996037605A3 WO1996037605A3 (fr) | 1996-12-27 |
Family
ID=10775100
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1996/000785 WO1996037605A2 (fr) | 1995-05-26 | 1996-05-24 | OLIGONUCLEOTIDES ANTISENS POUR BLOQUER LA SYNTHESE DU RECEPTEUR DE L'IgE |
Country Status (7)
Country | Link |
---|---|
US (1) | US5892023A (fr) |
EP (1) | EP0828827A2 (fr) |
AU (1) | AU6008296A (fr) |
CA (1) | CA2222197A1 (fr) |
GB (1) | GB9510718D0 (fr) |
NO (1) | NO975423D0 (fr) |
WO (1) | WO1996037605A2 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005085443A3 (fr) * | 2004-03-01 | 2006-03-16 | Massachusetts Inst Technology | Agents therapeutiques a base d'arni pour le traitement de la rhinite allergique et de l'asthme |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2408011A1 (fr) | 2000-05-04 | 2001-11-08 | Avi Biopharma, Inc. | Composition anti-sens a region d'epissage et methode associee |
US8370542B2 (en) * | 2002-09-16 | 2013-02-05 | Commvault Systems, Inc. | Combined stream auxiliary copy system and method |
CA2532795A1 (fr) * | 2003-08-07 | 2005-02-17 | Avi Biopharma, Inc. | Compose antiviral sens et methode permettant de traiter une infection virale induite par un arnss |
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US5770396A (en) * | 1992-04-16 | 1998-06-23 | The United States Of America As Represented By The Department Of Health And Human Services | Isolation characterization, and use of the human beta subunit of the high affinity receptor for immunoglobulin E |
IL111105A (en) * | 1993-09-30 | 2009-05-04 | Univ Pennsylvania | Use of a molecule capable of inhibiting the expression of syk kinase to prepare a pharmaceutical composition for inhibiting phagocytosis |
-
1995
- 1995-05-26 GB GBGB9510718.1A patent/GB9510718D0/en active Pending
-
1996
- 1996-05-24 EP EP96917549A patent/EP0828827A2/fr not_active Withdrawn
- 1996-05-24 WO PCT/FR1996/000785 patent/WO1996037605A2/fr not_active Application Discontinuation
- 1996-05-24 US US08/952,597 patent/US5892023A/en not_active Expired - Fee Related
- 1996-05-24 CA CA002222197A patent/CA2222197A1/fr not_active Abandoned
- 1996-05-24 AU AU60082/96A patent/AU6008296A/en not_active Abandoned
-
1997
- 1997-11-25 NO NO975423A patent/NO975423D0/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005085443A3 (fr) * | 2004-03-01 | 2006-03-16 | Massachusetts Inst Technology | Agents therapeutiques a base d'arni pour le traitement de la rhinite allergique et de l'asthme |
Also Published As
Publication number | Publication date |
---|---|
EP0828827A2 (fr) | 1998-03-18 |
WO1996037605A3 (fr) | 1996-12-27 |
NO975423L (no) | 1997-11-25 |
AU6008296A (en) | 1996-12-11 |
CA2222197A1 (fr) | 1996-11-28 |
US5892023A (en) | 1999-04-06 |
NO975423D0 (no) | 1997-11-25 |
GB9510718D0 (en) | 1995-07-19 |
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