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Antisense oligonucleotide modulation of STAT3 expression

An oligonucleotide and nucleic acid molecule technology, applied in the field of compositions for regulating the expression of human STAT3 gene, and DNA-binding proteins, which can solve the problems of incomplete selection of patients with multiple myeloma, etc.

Inactive Publication Date: 2007-02-14
IONIS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not entirely satisfactory options for treating patients with multiple myeloma

Method used

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  • Antisense oligonucleotide modulation of STAT3 expression
  • Antisense oligonucleotide modulation of STAT3 expression
  • Antisense oligonucleotide modulation of STAT3 expression

Examples

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preparation example Construction

[0082] 教授上面含磷键的制备的代表性美国专利包括但不限于美国专利:3,687,808;4,469,863;4,476,301;5,023,243;5,177,196;5,188,897;5,264,423;5,276,019;5,278,302;5,286,717;5,321,131;5,399,676;5,405,939;5,453,496;5,455,233;5,466,677 ;5,476,925;5,519,126;5,536,821;5,541,306;5,550,111;5,563,253;5,571,799;5,587,361;5,194,599;5,565,555;5,527,899;5,721,218;5,672,697和5,625,050,每项专利在文中引用作为参考。

[0083] In a more preferred embodiment of the invention, the oligomeric compound has one or more phosphorothioate linkages and / or heteroatom internucleoside linkages, in particular -CH 2 -NH-O-CH 2 -, -CH 2 -N(CH 3 )-O-CH 2 -[called methylene (methylimino) or MMI backbone], -CH 2 -O-N(CH 3 )-CH 2 -, -CH 2 -N(CH 3 )-N(CH 3 )-CH 2 -and-O-N(CH 3 )-CH 2 -CH 2 -[wherein the natural internucleotide phosphodiester bond is represented as -O-P(=O)(OH)-O-CH 2 -]. MMI-type internucleoside linkages are disclosed in US Patent 5,489,677, cited above. Preferred internucleotide amide linkages are disclosed in US Patent 5,602,240, ...

Embodiment 1

[0324] Example 1: Synthesis of oligonucleotides

[0325] Unmodified oligodeoxynucleotides were synthesized on an automated DNA synthesizer (Applied Biosystems, model 380B) using standard phosphoramidite chemistry via iodine oxidation. β-cyanoethyldiisopropyl-phosphoramidite was purchased from Applied Biosystems (Foster City, CA). For phosphorothioate oligonucleotides, the standard oxidation bottle was replaced with 0.2M in acetonitrile 3 H-1,2-Benzenedithiol-3-one 1,1-dioxide solution for stepwise thialation of phosphite bonds. The thiamination cycle wait step was increased to 68 seconds and followed by a capping step. The cytosine may be 5-methylcytosine (5-methyldeoxycytidine phosphoramidite is available from Glen Research, Sterling, VA or Amersham Pharmacia Biotech, Piscataway, NJ).

[0326] 2'-Methoxy β-cyanoethyldiisopropyl-phosphoramidite (Chemgenes, Needham, MA) and the standard cycle for unmodified oligonucleotides (except for the following pulse delivery of tetrazo...

Embodiment 2

[0375] Embodiment 2: human STAT3 oligodeoxynucleotide sequence

[0376]Antisense oligonucleotides targeting human STAT3 were designed. The target sequence data are from the APRF cDNA sequence published by Akira, S. et al. (Cell, 1994, 77, 63-71); GenBank _ Accession number L29277, herein SEQ ID NO:1. A series of oligodeoxynucleotides with phosphorothioate linkages were synthesized. 2'-Deoxycytosine is 5-methylcytosine. These oligonucleotide sequences are shown in Table 1. Another set of oligonucleotides was synthesized as chimeric oligonucleotides ("gapmers"), 20 nucleotides in length consisting of a central "gap" region containing 10 2'-deoxynucleotides and It consists of 5-nucleotide "wings" on both sides (5' and 3' directions). The wings consist of 2'-O-methoxyethyl (2'-MOE) nucleotides. The internucleoside (backbone) linkages are phosphorothioate linkages (P=S) throughout the oligonucleotide. All 2'-MOE cytosines and 2'-deoxycytosines are 5-methylcytosines. These o...

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Abstract

Compounds, compositions, and methods for inhibiting STAT3 expression are provided. The compositions comprise antisense oligonucleotides targeted to a nucleic acid encoding STAT3. Methods of inhibiting STAT3 expression and promoting apoptosis using these oligonucleotides are provided. Also provided are methods of treating diseases, particularly inflammatory diseases and cancers associated with STAT3 overexpression or constitutive activation or insufficient apoptosis.

Description

field of invention [0001] The present invention relates to compositions and methods for modulating the expression of the human STAT3 gene, which encodes a naturally occurring DNA-binding protein involved in signal transduction and transcriptional activation, and is involved in disease. The invention also relates to methods for inhibiting STAT3-mediated signal transduction and transcriptional activation; these methods can be used in diagnosis or therapy. Furthermore, the present invention relates to the treatment of diseases associated with human STAT3 gene expression. Background of the invention [0002] STAT protein (signal transducer and activator of transcription ( s signal t ransducers and a activators of t transcription)) are DNA-binding proteins with dual roles in signal transduction and transcriptional activation. Currently, there are six distinct STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6) and several isoforms (STAT1-α, STAT1-β, STAT3-α, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68C07H21/04A61K48/00C12N15/09A61K31/711A61K38/00A61P29/00A61P35/00A61P37/02A61P43/00C07H21/02C12N15/113C12Q1/02
CPCC12N2310/346C12N15/1135C12N2310/321C12N2310/341C12N2310/322A61K38/00C12N2310/315C12N15/113C12N2310/11C12N2310/3341Y02P20/582A61P19/02A61P29/00A61P35/00A61P35/02A61P37/02A61P43/00C12N2310/3525C12Q1/6883C12Q2600/136
Inventor J·G·卡拉斯
Owner IONIS PHARMA INC
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