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Oligomeric compounds for the modulation of survivin expression

A compound and analog technology, applied in the field of oligomeric compounds, can solve problems such as limiting the commercial value of analogs

Inactive Publication Date: 2006-03-15
圣塔里斯·法尔马公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And, in many cases, new complications have been discovered that severely limit the commercial value of many analogues

Method used

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  • Oligomeric compounds for the modulation of survivin expression
  • Oligomeric compounds for the modulation of survivin expression
  • Oligomeric compounds for the modulation of survivin expression

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0235] Embodiment 1: monomer synthesis

[0236] LNA monomer modules and their derivatives were constructed according to the following published procedures and references cited here, see:

[0237] ●WO 03 / 095467A1;

[0238] D. S. Pedersen, C. Rosenbohm, T. Koch (2002) Preparation of LNA Phosphoramidites, Synthesis 6, 802-808;

[0239] ●M.D.Sφensen, L.Kvaernφ, T.Bryid, A.E.Hakansson, B.Verbeure, G.Gaubert, P.Herdewijn, J.Wengel (2002) α-L-ribo-configured Locked Nucleic Acid (o-l-LNA): Synthesis and Properties, J. Am. Chem. Soc., 124, 2164-2176;

[0240] S.K.Singh, R.Kumar, J.Wengel (1998) Synthesis of Novel Bicyclo[2.2.1] Ribonucleosides: 2′-Amino-and 2′-Thio-LNA Monomeric Nucleosides, J.Org.Chem.1998, 63, 6078 -6079;

[0241]C. Rosenbohm, S.M.Christensen, M.D.Srensen, D.S.Pedersen, L.E.Larsen, J.Wengel, T.Koch (2003) Synthesis of 2'-amino-LNA: a newstrategy, Org.Biomol.Chem.1, 655-663 .

[0242] Synthesis of 2'-thio-LNA ribothymidine phosphoramidite. Reagents and Conditio...

Embodiment 2

[0288] Embodiment 2 synthetic oligonucleotides

[0289] Oligonucleotides were synthesized at 1 or 15 μmol using the phosphonimide method on an Expedite 8900 / MOSS synthesizer (Multiple Oligonucleotide Synthesis System, multi-step oligonucleotide synthesis system). At the end of the synthesis (DMT-on), oligonucleotides were cleaved from the solid support by using ammonia for 1 hour at room temperature and deprotected for 3 hours at 65°C. Oligonucleotides were purified by reverse phase HPLC (RP-HPLC). After removing the DMT group, the oligonucleotides were identified by IE-HPLC or RP-HPLC. Oligonucleotide identities were identified by ESI-MS. It will be described in detail below.

[0290] Preparation of LNA succinyl half ester

[0291] 5'-O-Dmt-3'-hydroxy-LNA monomer (500 mg), succinic anhydride (1.2 equiv) and dimethylaminopyridine (1.2 equiv) were dissolved in DCM (35 mL). The reaction was carried out overnight with shaking at room temperature. with NaH 2 PO 4 0.1M, pH5...

Embodiment 3

[0319] Example 3: Detection of designed oligomeric compounds

[0320] Our interest was to evaluate the antisense activity of different designs of oligonucleotides to demonstrate the importance of choosing the best design of nucleotides targeting survivin. For this purpose, we devised an in vitro assay that allowed us to screen different oligonucleotide designs by measuring the activity of firefly (Photinus pyralis) luciferase after downregulation with antisense oligonucleotides. Figure 1 contains an illustration of most of the designs mentioned in this paper. In the initial screen, designs containing β-D-oxy-LNA were evaluated, all of which targeted the motifs within the mRNAs being tested. Designs consisting of interpolymers with different gap sizes, different numbers of phosphorothioate internucleoside linkages, and different numbers of LNAs were examined. Headers and intermers with different numbers of β-D-oxy-LNA, different numbers of phosphorothioate internucleoside lin...

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Abstract

Oligonucleotides directed against the survivin gene are provided for modulating the expression of survivin. The compositions comprise oligonucleotides, particularly antisense oligonucleotides, targeted to nucleic acids encoding the survivin. Methods of using these compounds for modulation of survivin expression and for the treatment of diseases associated with either overexpression of survivin, expression of mutated survivin or both are provided. Examples of diseases are cancer such as lung, breast, colon, prostate, pancreas, lung, liver, thyroid, kidney, brain, testes, stomach, intestine, bowel, spinal cord, sinuses, bladder, urinary tract or ovaries cancers. The oligonucleotides may be composed of deoxyribonucleosides or a nucleic acid analogue such as for example locked nucleic acid or a combination thereof.

Description

technical field [0001] The invention provides compositions and methods for regulating the expression of Survivin. The invention particularly relates to oligomeric compounds, and preferably the compounds are oligonucleotides, which specifically hybridize to nucleic acids encoding survivin. These oligonucleotide compounds have been shown to regulate the expression of survivin, and their pharmaceutical preparation and application in the treatment of cancer diseases are disclosed. Background technique [0002] Cancer is a leading cause of death worldwide and encompasses a group of diseases caused by genetic disorders stemming from genome instability. All cancer cells are hypothesized to be defective in several regulatory pathways that control normal cell proliferation and homeostasis. These defects result in the ability to acquire various cancer cell-specific markers (Hanahan and Weinberg, 200, Cell 100, 57-70). One of these hallmarks of cancer is escape from the shackles of ...

Claims

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Application Information

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IPC IPC(8): C12N15/11A61K31/7088A61P35/00
Inventor 波·汉森夏洛特·阿尔巴克·特荣卡米尔·杜蒙·彼德森马伊肯·韦尔特加德玛吉特·维森巴赫
Owner 圣塔里斯·法尔马公司
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