Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-07-17
2002-08-27
LeGuyader, John L. (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S006120, C435S091100, C435S325000, C435S366000, C536S023100, C536S024310, C536S024330, C536S024500
Reexamination Certificate
active
06440739
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Glioma-associated oncogene-2. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Glioma-associated oncogene-2. Such compounds have been shown to modulate the expression of Glioma-associated oncogene-2.
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. Overexpression of transcription factor genes can lead to aberrant regulation of cellular processes and consequently to pathologic phenotypes.
One such family of transcription factors are the zinc finger proteins. Zinc finger proteins contain a diverse set of motifs that bind zinc ions in order to stabilize the structure of a small, autonomously folded protein domain. The term “zinc finger” is derived from the original discovery that zinc-binding mini-domains are used to grip the DNA of the regulatory region of the 5S RNA gene. Although other zinc finger modules are used for a variety of functions, the most common role is to serve as DNA-binding domains within transcription factors (Klug and Schwabe,
Faseb J.,
1995, 9, 597-604).
The genes of the GLI family encode zinc-finger-containing transcription factors which act at the last known step in the hedgehog signal-transduction pathway. The human glioma-associated oncogene-1 gene was originally isolated from a human glioma cell line (Kinzler et al.,
Science,
1987, 236, 70-73). Subsequently, glioma-associated oncogenes-2 and -3 were isolated on the basis of homology of their zinc finger regions with glioma-associated oncogene-1 (Ruppert et al.,
Molecular and Cellular Biology,
8, 3104-3113). The genes of the GLI family are involved in cell-fate determination, proliferation and patterning in many cell types and most organs (Ruiz,
Nat. Cell Biol.,
1999, 1, E147-148).
Glioma-associated oncogene-3 (also known as GLI-3) has been implicated in hedgehog signaling, a pathway with critical functions during embryogenesis of both invertebrate and vertebrate species (Ruiz,
Nat. Cell Biol.,
1999, 1, E147-148). It is expressed widely in populations of cells which are responsive to hedgehog signaling.
Originally cloned by Ruppert, et al., (Ruppert et al.,
Molecular and Cellular Biology,
8, 3104-3113) human glioma-associated oncogene-3 has been mapped to chromosome 2q14 (Matsumoto et al.,
Genomics,
1996, 36, 220-221).
Four isoforms of human glioma-associated oncogene-2, known as hGli2 &agr;, &bgr;, &ggr;, and &dgr; are formed from combinations of two independent splicing processes (Tanimura et al.,
J. Virol.,
1998, 72, 3958-3964). These isoforms have been implicated in enhancement of the processes leading to transcription of proteins of the human T-cell leukemia virus (Tanimura et al.,
J. Virol.,
1998, 72, 3958-3964).
Deregulation of the hedgehog pathway is responsible for several human developmental syndromes and malformations, including holoprosencephaly, Greig's cephalopolysyndactyly, Pallister-Hall syndrome, Rubenstein-Teybi syndrome, basal cell nevoid syndrome and post-axial polydactyly (Ruiz i Altaba,
Trends Genet.,
1999, 15, 418-425). In addition, cancers including basal cell carcinoma, medulloblastoma and rhabdomyosarcoma are linked to abnormal function of the hedgehog pathway (Ruiz i Altaba,
Trends Genet.,
1999, 15, 418-425).
Transgenic mice overexpressing glioma-associated oncogene-2 in cutaneous keratinocytes develop multiple basal cell carcinomas, implicating it in a central role in the genesis of these tumors (Grachtchouk et al.,
Nat. Genet.,
2000, 24, 216-217).
The pharmacological modulation of glioma-associated oncogene-2 activity and/or expression may therefore be an appropriate point of therapeutic intervention in developmental syndromes and cancers.
Strategies aimed at investigating glioma-associated oncogene-2 function have involved the use of truncated mutants for definition of context-dependent positive and negative roles of the gene (Sasaki et al.,
Development
(Cambridge, U. K.), 1999, 126, 3915-3924).
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of glioma-associated oncogene-2. Consequently, there remains a long felt need for agents capable of selectively and effectively modulating the expression of glioma-associated oncogene-2.
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-2 expression.
The present invention provides compositions and methods for modulating glioma-associated oncogene-2 expression as well as alternatively spliced forms of glioma-associated oncogene-2 including, but not limited to, hGli &agr;, hGli &bgr;, hGli &ggr;, and hGli &dgr;.
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-2, and which modulate the expression of Glioma-associated oncogene-2. 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-2 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-2 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-2, ultimately modulating the amount of Glioma-associated oncogene-2 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Glioma-associated oncogene-2. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Glioma-associated oncogene-2” encompass DNA encoding Glioma-associated oncogene-2, 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-2. 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 nucle
Bennett C. Frank
Freier Susan M.
ISIS Pharmaceuticals Inc.
LeGuyader John L.
Licata & Tyrrell P.C.
Schmidt Mary
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