Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-06-17
2004-06-01
Lacourciere, Karen A. (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S091100, C435S325000, C435S375000, C435S366000, C536S023100, C536S024300, C536S024330, C514S04400A
Reexamination Certificate
active
06743909
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of PTPN12. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding PTPN12. Such compounds have been shown to modulate the expression of PTPN12.
BACKGROUND OF THE INVENTION
The process of phosphorylation, defined as the attachment of a phosphate moiety to a biological molecule through the action of enzymes called kinases, represents one course by which intracellular signals are propagated resulting finally in a cellular response. Within the cell, proteins can be phosphorylated on serine, threonine or tyrosine residues and the extent of phosphorylation is regulated by the opposing action of phosphatases, which remove the phosphate moieties. While the majority of protein phosphorylation within the cell is on serine and threonine residues, tyrosine phosphorylation is modulated to the greatest extent during oncogenic transformation and growth factor stimulation (Zhang,
Critical Review in Biochemistry and Molecular Biology,
1998, 33, 1-52).
Because phosphorylation is such a ubiquitous process within cells and because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation of, or functional mutations in, kinases and phosphatases. Consequently, considerable attention has been devoted recently to the characterization of tyrosine kinases and tyrosine phosphatases.
PTPN12 (also known as protein tyrosine phosphatase, non-receptor type 12, PTP-PEST and protein tyrosine phosphatase G1; PTPG1) was first cloned from human colon tissue (Takekawa et al.,
Biochem. Biophys. Res. Commun.,
1992, 189, 1223-1230) and human skeletal muscle and (Yang et al.,
J. Biol. Chem.,
1993, 268, 6622-6628) and subsequently found in a variety of human cell lines (Yang et al.,
J. Biol. Chem.,
1993, 268, 6622-6628). It shares 36% identity with the placental PTP1B enzyme (Cool et al.,
Proc. Natl. Acad. Sci. USA,
1989, 86, 5257-5261; Yang et al.,
J. Biol. Chem.,
1993, 268, 6622-6628) which has an essential regulatory role in signaling mediated by the insulin receptor (Goldstein et al.,
Mol. Cell. Biochem.,
1998, 182, 91-99). The major distinguishing feature of PTPN12 is a hydrophilic C-terminal segment rich in proline, glutamate, aspartate, serine and threonine amino acid residues arranged in motifs known as PEST sequences which are thought to cause rapid turnover of PEST-containing proteins in vivo (Yang et al.,
J. Biol. Chem.,
1993, 268, 6622-6628).
In 1994 the PTPN12 gene was mapped to chromosome 7q11.23, a region with frequent abnormalities implicated in malignant melanoma, and residing near recurrent breakpoints of chromosomal rearrangements found in tumor cells. In addition, allelic deletions of 7q have been reported in solid tumors including colorectal carcinomas. Abnormalities of this locus may be associated with these disorders are a result of alterations in the PTPN12 gene (Takekawa et al.,
FEBS Lett.,
1994, 339, 222-228). Three aberrant mRNA transcripts of PTPN12 have been identified in colon carcinoma cells, including two mRNA transcripts which are predicted to encode PTPN12 proteins prematurely truncated in the phosphatase domain (Takekawa et al.,
FEBS Lett.,
1994, 339, 222-228).
PTPN12 has been implicated in signaling events influencing the execution phase of apoptosis via association with the cytoskeletal proteins paxillin (Song et al.,
Free Radical Biol. Med.,
2000, 29, 61-70), and p130cas (Garton et al.,
Mol. Cell. Biol.,
1996, 16, 6408-6418), focal adhesion phosphoproteins responsible for the recruitment of structural and signaling molecules to focal adhesions (Song et al.,
Free Radical Biol. Med.,
2000, 29, 61-70). Hic-5, a homologue of paxillin has also been found to act as a regulator of PTPN12 in mouse fibroblasts (Nishiya et al.,
J. Biol. Chem.,
1999, 274, 9847-9853).
It was subsequently found that PTPN12's proline-rich sequences constitute specific binding sites for the src homology 3 (SH3) domains of p130cas (Garton et al.,
Oncogene,
1997, 15, 877-885). Additionally, investigations of murine PTPN12 have indicated that the proline-rich domains provide the basis for interactions involved in recruitment of PTPN12 to activated epidermal growth factor (EGF) receptors, thus implicating PTPN12 in EGF receptor-mediated signal transduction events (Charest et al.,
Oncogene,
1997, 14, 1643-1651).
The involvement of PTPN12 in cell signaling events and proliferation make it a potentially useful therapeutic target for intervention in hyperproliferative disorders and disorders arising from aberrant apoptosis.
Disclosed and claimed in U.S. Pat. No. 6,087,109 are conjugated compounds comprised of an ST receptor-binding moiety and an antisense molecule for the purpose of targeting PTPN12 and other genes involved in colorectal cancer (Waldman, 2000).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of PTPN12.
To date, investigative strategies aimed at modulating PTPN12 function have involved the use of ST receptor-binding moieties conjugated to antisense molecules and the protein Hic-5. However, they have yet to be tested as therapeutic protocols.
Consequently, there remains a long felt need for agents capable of effectively inhibiting PTPN12 function.
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 PTPN12 expression.
The present invention provides compositions and methods for modulating PTPN12 expression, including modulation of truncated forms of PTPN12.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding PTPN12, and which modulate the expression of PTPN12. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of PTPN12 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 PTPN12 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 PTPN12, ultimately modulating the amount of PTPN12 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding PTPN12. As used herein, the terms “target nucleic acid” and “nucleic acid encoding PTPN12” encompass DNA encoding PTPN12, 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, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, 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 fa
Cowsert Lex M.
Dobie Kenneth W.
Gibbs Terra C.
ISIS Pharmaceuticals Inc.
Lacourciere Karen A.
Licata & Tyrrell P.C.
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