Antisense modulation of glioma-associated oncogene-1 expression

Details Antisense modulation of glioma-associated oncogene-1 expression Antisense modulation of glioma-associated oncogene-1 expression

2000-09-08

2001-12-11

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C536S023100, C536S024100, C536S024310, C536S024500, C514S04400A, C435S006120, C435S091100, C435S320100, C435S325000, C435S366000

Reexamination Certificate

active

06329203

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of glioma-associated oncogene-1. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding glioma-associated oncogene-1. Such compounds have been shown to modulate the expression of glioma-associated oncogene-1.
BACKGROUND OF THE INVENTION
Transcription factors represent a group of molecules within the cell that function to connect the pathways from extracellular signals to intracellular responses.
Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind to specific DNA sequences in the promoter elements of target genes and activate the transcription of these target genes.
Glioma-associated oncogene-1 (also known as GLI and GLI-1) is a nuclear protein containing 5 zinc fingers connected by a highly conserved sequence of 7 amino acids termed the H/C link, a region which has homology to the Kruppel family of zinc finger transcription factors (Kinzler et al.,
Nature,
1988, 332, 371-374). The isolation of other GLI-related proteins has lead to the classification of these proteins into a separate sub-family of transcription factors, the Kruppel-related gene family or the GLI-Kruppel family. Seven members of the family have been isolated in humans; four of which are GLI proteins (Ruppert et al.,
Mol. Cell. Biol.,
1988, 8, 3104-3113).
Glioma-associated oncogene-1 was originally cloned from a glioma cell line where it was shown to be amplified more than 50-fold (Kinzler et al.,
Science,
1987, 236, 70-73; Kinzler et al.,
Nature,
1988, 332, 371-374). In fact, expression of the protein in the central nervous system is a rare event and the elevated levels observed are associated with amplification of the gene (Xiao et al.,
Pediatr. Neurosurg.,
1994, 20, 178-182). Subsequently it been shown to have oncogenic potential in other cell types (Ruppert et al.,
Mol. Cell. Biol.,
1991, 11, 1724-1728). Additionally, the glioma-associated oncogene-1 gene is located in a chromosomal region that is affected by translocations in a variety of benign and malignant tumors (Kinzler et al.,
Science,
1987, 236, 70-73).
Overexpression of glioma-associated oncogene-1 has been demonstrated in all sporadic human basal cell carcinomas examined (Dahmane et al.,
Nature,
1997, 389, 876-881) as well as in medulloblastoma and rhabdomyosarcomas in mutant mice (Hahn et al.,
J. Mol. Med.,
1999, 77, 459-468). It is also amplified in several childhood sarcomas including osteosarcoma, rhabdomyosarcoma and liposarcoma (Roberts et al.,
Cancer Res.,
1989, 49, 5407-5413).
The pharmacological modulation of glioma-associated oncogene-1 activity and/or expression may therefore be an appropriate point of therapeutic intervention in pathological conditions such as cancers of the central nervous system, skin and musculoskeletal system.
To date, strategies aimed at investigating glioma-associated oncogene-1 function have involved the use of antibodies and immunohistochemical methods to identify expression patterns and cellular localization (Ghali et al.,
J. Invest. Dermatol.,
1999, 113, 595-599). Truncated mutants of the GLI proteins have also been used to define the context-dependent positive and negative roles of the individual members of the family (
Altaba, Development,
1999, 126, 3205-3216).
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of glioma-associated oncogene-1. Consequently, there remains a long felt need for these agents.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of glioma-associated oncogene-1 expression.
The present invention provides compositions and methods for modulating glioma-associated oncogene-1 expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding glioma-associated oncogene-1, and which modulate the expression of glioma-associated oncogene-1. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of glioma-associated oncogene-1 in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of glioma-associated oncogene-1 by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding glioma-associated oncogene-1, ultimately modulating the amount of glioma-associated oncogene-1 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding glioma-associated oncogene-1. As used herein, the terms “target nucleic acid” and “nucleic acid encoding glioma-associated oncogene-1” encompass DNA encoding glioma-associated oncogene-1, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of glioma-associated oncogene-1. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding glioma-associated oncogene-1. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or

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