Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-04-28
2001-06-05
LeGuyader, John L. (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S024300, C536S024310, C536S024330, C514S04400A, C435S006120, C435S325000, C435S375000
Reexamination Certificate
active
06242590
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of zinc finger protein-217. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding zinc finger protein-217. Such oligonucleotides have been shown to modulate the expression of zinc finger protein-217.
BACKGROUND OF THE INVENTION
Transcription factors represent a group of molecules within the cell that function to connect 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 or genomic amplification of transcription factor genes can lead to aberrant regulation of cellular processes and consequently to pathologic phenotypes. Studies using comparative genomic hybridization have revealed a number of chromosomal regions of recurrent amplification of copy number in breast tumors while other studies have detected amplification events associated with cancers of the ovary, colon, head and neck, brain and pancreas (Isola et al.,
Am. J. Pathol.,
1995, 147, 905-911; Kallioniemi et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1994, 91, 2156-2160; Kallioniemi et al.,
Genes Chromosomes Cancer,
1994, 10, 231-243)
Zinc finger protein-217 (also known as ZNF217 and ZABC1) was recently identified as a potential transcription factor that is located in a genomic region of recurrent amplification on chromosome 20q13.2 (Collins et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1998, 95, 8703-8708). Amplification in this chromosomal region has been shown to occur in a variety of tumor types and has been associated with aggressive tumor behavior, especially in invasive breast cancers (Tanner et al.,
Clin. Cancer Res.,
1995, 1, 1455-1461).
Characterization of the protein revealed that zinc finger protein-217 encodes an alternatively spliced protein of either 1062 or 1108 amino acids and contains eight C2H2 zinc finger Kruppel-like DNA-binding motifs. Kruppel-like transcription factors have been implicated in several human malignancies. In addition, the protein contains a proline rich domain and these have been shown to function as transcriptional activators (Collins et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1998, 95, 8703-8708).
The pharmacological modulation of zinc finger protein-217 activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in pathological conditions. Currently, there are no known therapeutic agents which effectively inhibit the synthesis of zinc finger protein-217 and 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 zinc finger protein-217 expression.
The present invention provides compositions and methods for modulating zinc finger protein-217 expression, including modulation of the alternatively spliced form of zinc finger protein-217.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding zinc finger protein-217, and which modulate the expression of zinc finger protein-217. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of zinc finger protein-217 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 zinc finger protein-217 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 antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding zinc finger protein-217, ultimately modulating the amount of zinc finger protein-217 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding zinc finger protein-217. As used herein, the terms “target nucleic acid” and “nucleic acid encoding zinc finger protein-217” encompass DNA encoding zinc finger protein-217, 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 zinc finger protein-217. 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 zinc finger protein-217. 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 the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start cod
Epps Janet
ISIS Pharmaceuticals Inc.
LeGuyader John L.
Licata & TyrrellP.C.
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