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Modulation of survivin expression

A technology for survivin and chain compounds, which is applied in the field of compositions for regulating survivin expression, and can solve the problems of reduced sequence specificity of gene expression and the like

Inactive Publication Date: 2007-06-20
IONIS PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This phenomenon of post-transcriptional gene silencing has been termed "RNA interference (RNAi)" and the phenomenon has come to refer broadly to gene silencing processes involving dsRNA, which lead to a sequence-specific reduction in gene expression by degrading target mRNA (Tuschl et al. People, Genes Dev., 1999, 13, 3191-3197)

Method used

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  • Modulation of survivin expression
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Examples

Experimental program
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Effect test

Embodiment 1

[0264] Example 1: Nucleoside phosphoramidite for oligonucleotide synthesis

[0265] Deoxy and 2’-alkoxy amide salt

[0266] 2'-deoxy and 2'-methoxy β-cyanoethyl diisopropyl phosphoramidite are purchased from commercial sources (e.g., Chemgenes, Needham, MA or Glen Research, Inc. Sterling, VA). Other 2'-alkoxy substituted nucleoside amide salts are prepared as described in U.S. Patent No. 5,506,351, which is incorporated herein by reference. To synthesize oligonucleotides using 2'-alkoxy amide salts, a standard cycle of unmodified oligonucleotides was used, except that the waiting step after pulsed delivery of tetrazole and bases was increased to 360 seconds.

[0267] Commercially available phosphoramidites (Glen Research, Sterling VA or ChemGenes, Needham, MA) were synthesized according to published methods (Sanghvi et al., Nucleic Acids Research, 1993, 21, 3197-3203) containing 5-methyl -2'-deoxycytidine (5-Me-C) oligonucleotide.

[0268] 2'-fluoroamide salt

[0269] 2'-Fluorodeo...

Embodiment 2

[0299] Example 2: Oligonucleotide synthesis

[0300] Unsubstituted and substituted phosphodiester (P=O) oligonucleotides were synthesized on an automatic DNA synthesizer (Applied Biosystems model 380B) using standard phosphoramidite chemistry and iodine oxidation.

[0301] In addition to using a 0.2M solution of 3H-1,2-benzodithiol-3-one 1,1-dioxide in acetonitrile to replace the standard oxidation bottle for the stepwise vulcanization of the phosphite bond, Phosphorothioate was synthesized in the same way as phosphodiester oligonucleotides. The thiohybridization waiting step was increased to 68 seconds and was followed by a capping step. After the oligonucleotide was cut from the CPG column and deprotected in concentrated ammonium hydroxide at 55°C (18 hours), the oligonucleotide was purified by precipitation with 2.5 times the volume of ethanol in a 0.5 M NaCl solution. The phosphinate oligonucleotides were prepared as described in U.S. Patent 5,508,270, which is incorporated he...

Embodiment 3

[0309] Example 3: Oligonucleoside synthesis

[0310] As described in U.S. Patent Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240, and 5,610,289, methylene methyl imino-linked oligonucleosides were prepared, which were also confirmed to be MMI-linked oligonucleosides, methylene dimethyl oligonucleosides. Amino oligonucleosides, which are also confirmed as MDH-linked oligonucleosides, and methylene carbonyl amino-linked oligonucleosides, which are also confirmed as amide-3 linked oligonucleosides, and methylene aminocarbonyl-linked oligonucleosides Nucleosides, which are also identified as amide-4 linked oligonucleosides, and mixed backbone compounds with, for example, alternating MMI and P=O or P=S bonds, all patents are hereby incorporated by reference. The oligomeric compound of the present invention may also contain a mixed bond. In the mixed bond, any number of two or more bonds can appear in any order and appear at any position in the oligomeric compound, for example, it conta...

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Abstract

Compounds and compositions are provided for modulating the expression of survivin. The compounds, exemplified by those acting through an RNAi antisense mechanism of action, include double-stranded and single-stranded constructs, as well as siRNAs, canonical siRNAs, blunt-ended siRNAs and single-stranded antisense RNA compounds. Methods of using these compounds for modulation of survivin expression and for treatment of diseases associated with expression of survivin are provided.

Description

Invention field [0001] The present invention provides compositions and methods for regulating the expression of survivin. In particular, the present invention relates to antisense compounds that specifically hybridize with nucleic acid encoding human survivin, especially double-stranded oligonucleotides. It has been demonstrated that these oligonucleotides can regulate the expression of survivin. Background of the invention [0002] The characteristic feature of cancerous cells is uncontrolled proliferation. One of the differences between tumors and normal cells that has been discovered is resistance to the process of programmed cell death, also called apoptosis (Ambrosini et al., Nat. Med., 1997, 3, 917-921). Apoptosis is a process that multicellular organisms have evolved to prevent uncontrolled cell proliferation and eliminate cells that are diseased, harmful, or no longer needed. The apoptotic process involves a multi-step cascade in which cells are degraded from the inside t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/04C12N15/00A61K48/00A61KC12N15/113
CPCC12N15/1135C12N2310/14C12N2310/315C12N2310/321C12N2310/322A61P35/00A61P43/00
Inventor B·巴特B·K·帕泰特E·斯韦兹
Owner IONIS PHARMA INC
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