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Methods and compositions for the inhibition of gene expression

Inactive Publication Date: 2005-12-29
PRONAI THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014] The present invention additionally provides a composition comprising an oligonucleotide that hybridizes under physiological conditions to the promoter region of a c-ki-Ras gene located on a chromosome of a cell under conditions such that proliferation of the cell is reduced.

Problems solved by technology

This makes protein-based drugs ineffective since their specificity involves ligand-receptor recognition.
However, this modification can only slow the degradation of antisense and therefore large dosages of antisense drug are required to be effective.
Despite the optimism surrounding the use of antisense therapies, there are a number of serious problems with the use of antisense drugs such as difficulty in getting a sufficient amount of antisense into the cell, non-sequence-specific effects, toxicity due to the large amount of sulfur containing phosphothioates oligonucleotides and their inability to get into their target cells, and high cost due to continuous delivery of large doses.
An additional problem with antisense drugs has been their nonspecific activities.

Method used

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  • Methods and compositions for the inhibition of gene expression
  • Methods and compositions for the inhibition of gene expression
  • Methods and compositions for the inhibition of gene expression

Examples

Experimental program
Comparison scheme
Effect test

example 1

Materials and Methods

[0211] This Example describes experimental methods utilized in the below examples.

A. Cell Lines

[0212] Cell lines used in experiments of the present invention are described below.

MDA-MB-231

[0213] Tissue: adenocarcinoma; mammary gland; breast; pleural effusion [0214] Tumorigenic: forms adenocarcinoma grade III [0215] Receptors expressed: Epidermal Growth Factor (EGF) and Transforming growth factor (TGF-alpha) [0216] Oncogene: wnt3+ and wnt7h+

References: [0217] Siciliano M J, Barker P E, Cailleau R. Mutually exclusive genetic signatures of human breast tumor cell lines with a common chromosomal marker. Cancer Res. March 1979;39(3):919-22. [0218] Calleau R, Olive M, Cruciger Q V. Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization. In vitro. November 1978;14(11):911-5. [0219] Cruciger Q V, Pathak S, Calleau R. Human breast carcinomas: marker chromosomes involving 1q in seven cases. Cytogenet Cell Genet. 1976; 17(4)...

example 2

c-ki-RAS

[0279] This example describes the ability of oligonucleotide compounds targeted against the promoter of the c-ki-Ras gene to inhibit the growth of cancer cell lines. Experiments were performed as described in Example 1. The results are shown in FIGS. 13 and 19. The sequences of the oligonucleotides targeted against c-ki-Ras as well as the sequence of c-ki-Ras gene are shown in FIGS. 5 and 6.

example 3

Bcl-2

[0280] This example describes the ability of oligonucleotide compounds targeted against the promoter of the bcl-2 gene to inhibit the growth of cancer cell lines. Experiments were performed as described in Example 1. The results are shown in FIGS. 14 and 20. The sequences of the oligonucleotides targeted against bcl-2 as well as the sequence of bcl-2 gene are shown in FIGS. 1 and 2.

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Abstract

The present invention relates to methods and compositions for the inhibition of gene expression. In particular, the present invention provides oligonucleotide-based therapeutics for the inhibition of oncogenes involved in cancers.

Description

FIELD OF THE INVENTION [0001] The present invention relates to methods and compositions for the inhibition of gene expression. In particular, the present invention provides oligonucleotide-based therapeutics for the inhibition of oncogenes involved in cancers. BACKGROUND OF THE INVENTION [0002] Oncogenes have become the central concept in understanding cancer biology and may provide valuable targets for therapeutic drugs. All oncogenes and their products operate inside the cell. This makes protein-based drugs ineffective since their specificity involves ligand-receptor recognition. [0003] Antisense oligodeoxyribonucleotides (oligonucleotides) are under investigation of therapeutic compound for specifically targeting oncogenes (Wickstrom, E. (ed). Prospects for antisense nucleic acid therapy of cancer and Aids. New York: Wiley-Liss, Inc. 1991; Murray, J. A. H. (ed). Antisense RNA and DNA New York: Wiley-Liss, Inc. 1992). Antisense drugs are modified synthetic oligonucleotides that wo...

Claims

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Application Information

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IPC IPC(8): A61K48/00C12N15/113C12N15/85C12N15/88
CPCA61K31/70A61K48/00C12N2310/3341C12N2310/11C12N15/1135A61P35/00A61P35/02
Inventor SHEIKHNEJAD, REZASOOCH, MINAGOODWIN, NEALOLSON, DAVID
Owner PRONAI THERAPEUTICS INC
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