Antisense modulation of PTPN2 expression

Details Antisense modulation of PTPN2 expression Antisense modulation of PTPN2 expression

2001-05-18

2002-11-26

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S006120, C435S325000, C536S023100, C536S024300, C536S024310, C536S024330, C536S024500

Reexamination Certificate

active

06485974

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of PTPN2. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding PTPN2. Such compounds have been shown to modulate the expression of PTPN2.
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,
Crit. Rev. Biochem. Mol. Biol
., 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.
PTPN2 (also known as protein tyrosine phosphatase, non-receptor type 2, TC-PTP, TCELLPTP and PTPT) is expressed ubiquitously but is present in higher amounts in placenta and cells of lymphoid lineage (Ibarra-Sanchez et al.,
Semin. Immunol
., 2000, 12, 379-386). It shares 65% identity with the placental PTP1B enzyme (Cool et al.,
Proc. Natl. Acad. Sci. U S A
, 1989, 86, 5257-5261) which has an essential regulatory role in signaling mediated by the insulin receptor (Goldstein et al.,
Mol. Cell. Biochem
., 1998, 182, 91-99).
The human PTPN2 gene was first isolated in 1989 (Cool et al.,
Proc. Natl. Acad. Sci. U S A
, 1989, 86, 5257-5261) and was later mapped to chromosome 18p11.2-11.3 (Sakaguchi et al.,
Genomics
, 1992, 12, 151-154).
Disclosed and claimed in PCT publication WO 91/13989 are DNA sequences encoding PTPN2 (Fischer et al., 1991).
The murine equivalent of PTPN2 has been named both MPTP and PTP-2 while the rat gene has been assigned the name PTP-S (Ibarra-Sanchez et al.,
Semin. Immunol
., 2000, 12, 379-386).
PTPN2 has a modular structure consisting of an N-terminal catalytic domain and a non-catalytic C-terminal segment. Expression of human PTPN2 in baby hamster kidney (BHC) cells led to the finding that a 48-KDa PTPN2 is primarily located in the particulate fraction of cell extracts while a 37-KDa form of the protein (also known as delta C11.PTP) lacking an 11-KDa C-terminal extension of PTPN2 is soluble (Cool et al.,
Proc. Natl. Acad. Sci. U S A
, 1990, 87, 7280-7284). These results suggest that the C-terminal segment is important in determining the localization and regulation of PTPN2 (Cool et al.,
Proc. Natl. Acad. Sci. U S A
, 1990, 87, 7280-7284). Overexpression of this truncated 37-KDa form of PTPN2 in Rat 2 cells transformed with the v-fms oncogene led to the finding that the 37-KDa PTPN2 is capable of suppressing the oncogenic properties of the v-fms oncogene and reducing the growth rate of the cells to 50% of that observed when the v-fms-transformed cells were transfected with the full length PTPN2 (Zander et al.,
Oncogene
, 1993, 8, 1175-1182).
The physiological role of PTPN2 has remained elusive but the recent generation of mouse PTPN2 knockout models has highlighted the importance of this gene in the immune system. The knockout mice exhibit deficient T and B cell proliferative responses and defects in B cell ontogeny and erythroid development in the bone marrow due to an inability of stromal cells to support normal hematopoiesis (You-Ten et al.,
J. Exp. Med
., 1997, 186, 683-693). You-ten et al. have also suggested that the impaired bone marrow microenvironment may be a result of reduced numbers of stromal cells, impaired function of stromal cells or inadequate production of cytokines, indicating that PTPN2 plays a significant role in both hematopoiesis and immune function (You-Ten et al.,
J. Exp. Med
., 1997, 186, 683-693).
In addition to the situation involving the truncation of the protein, alternative splicing of the human PTPN2 mRNA gives rise to a 45 KDa protein that lacks the hydrophobic segment at the C-terminus and results in its localization in the nucleus whereas the full-length 48 KDa protein is targeted to the endoplasmic reticulum (Lorenzen et al.,
J. Cell Biol
., 1995, 131, 631-643). It has been recently discovered that the 45-KDa protein (also known as TC45) is involved in regulation of epidermal growth factor receptor-mediated signaling and phosphatidylinositol 3-kinase-dependent signaling and thus may serve as an important target for intervention in tumors where excessive signaling via these pathways contributes to the disease (Tiganis et al.,
J. Biol. Chem
., 1999, 274, 27768-27775).
The involvement of PTPN2 in immune system regulation and cell proliferation make it a potentially useful therapeutic target for intervention in autoimmune diseases, hematopoietic diseases and hyperproliferative disorders. Currently, there are no known agents capable of modulating expression and/or function of PTPN2. Consequently, there remains a long felt need for agents capable of effectively inhibiting PTPN2 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 PTPN2 expression.
The present invention provides compositions and methods for modulating PTPN2 expression, including modulation of alternatively spliced forms of PTPN2 as well as the truncated form.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding PTPN2, and which modulate the expression of PTPN2. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of PTPN2 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 PTPN2 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 PTPN2, ultimately modulating the amount of PTPN2 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding PTPN2. As used herein, the terms “target nucleic acid” and “nucleic acid encoding PTPN2” encompass DNA encoding PTPN2, 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

Affiliated with

Also associated with

Rating

Antisense modulation of PTPN2 expression does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Antisense modulation of PTPN2 expression, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antisense modulation of PTPN2 expression will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2931223