Antisense inhibition of dual specific phosphatase 9 expression

Details Antisense inhibition of dual specific phosphatase 9 expression Antisense inhibition of dual specific phosphatase 9 expression

2001-08-01

2003-05-20

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C514S04400A, C536S024500, C536S023100

Reexamination Certificate

active

06566133

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Dual specific phosphatase 9. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Dual specific phosphatase 9. Such compounds have been shown to modulate the expression of Dual specific phosphatase 9.
BACKGROUND OF THE INVENTION
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are tightly regulated and often overlap as evidenced by the existence of multiple protein kinase and phosphatase families and isoforms. 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 or functional mutations in the molecular components of these cascades. Consequently, considerable attention has been devoted to the characterization of proteins exhibiting either kinase or phosphatase enzymatic activity.
The magnitude and duration of signaling through mitogen-activated kinases (MAP kinases) and stress-activated kinases relay, amplify and integrate signals from a diverse range of stimuli and elicit an appropriate physiological response. In mammalian systems, these responses include cellular proliferation, differentiation, development, inflammatory responses and apoptosis (Keyse,
Current Opinion in Cell Biology,
2000, 12, 186-192).
Regulation of the signaling activities of MAP kinases and stress-activated kinases is dependent upon a balance between the activities of upstream activators and a complex network of protein phosphatases. These MAP kinase phosphatases include a class known as the dual specific (or dual specificity) phosphatases which dephosphorylate tyrosine and threonine residues on the same substrate. The dual specific phosphatases can be divided into two groups, the inducible nuclear enzymes, and the cytosolic enzymes (Keyse,
Current Opinion in Cell Biology,
2000, 12, 186-192).
First cloned in 1997 (Muda et al.,
J. Biol. Chem.,
1997, 272, 5141-5151), dual specific phosphatase 9 (also known as DUSP9, DSP9 and MAP kinase phosphatase 4; MKP-4) belongs to the cytosolic dual specific phosphatase group (Keyse,
Current Opinion in Cell Biology,
2000, 12, 186-192). It is expressed as a 2.5 kb mRNA in placenta, kidney and fetal liver (Muda et al.,
J. Biol. Chem.,
1997, 272, 5141-5151). Dual specific phosphatase 9 displays relatively nonselective activity toward MAP kinases and stress-activated kinases including extracellular signal-regulated kinases (ERKs), p38 MAP kinase and c-Jun NH
2
-terminal kinase/stress activated kinase (JNK/SAPK).
Disclosed and claimed in the PCT publication WO 00/60100 are nucleic acid sequences encoding dual specific phosphatase 9 (Luche and Wei, 2000). Also claimed are antisense polynucleotides at least 15 nucleotides in length complementary to dual specific phosphatase 9, antibodies and methods for the detection of dual specific phosphatase as well as methods for the modulation of certain cellular processes within a cell (Luche and Wei, 2000).
The potential role of dual specific phosphatase 9 as a regulator of MAP kinase or JNK/SAPK activity indicates that its selective inhibition may be a potential strategy with which to derive treatments for hyperproliferative disorders, developmental disorders, inflammatory disorders and diseases arising from aberrant apoptosis.
Generally claimed in PCT publication WO/60100 are antisense polynucleotides comprised of at least 15 consecutive nucleotides complementary to polynucleotides encoding dual specific phosphatase 9. In addition, generally claimed is an isolated antibody or antigen binding fragment thereof, that binds to dual specific phosphatase 9 (Luche and Wei, 2000).
Examples of various small molecule inhibitors of dual specific phosphatases exist in the art. For example, Rice et al. have synthesized a library of general dual specific phosphatase inhibitors based on a central oxazole pharmacophore (Rice et al.,
Biochemistry,
1997, 36, 15965-15974). To date however, there are no other known examples of specific and selective inhibitors of dual specific phosphatase 9. Consequently, there remains a long felt need for agents capable of effectively and selectively inhibiting the function of dual specific phosphatase 9.
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 expression of dual specific phosphatase 9.
The present invention provides compositions and methods for modulating expression of dual specific phosphatase 9.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding Dual specific phosphatase 9, and which modulate the expression of Dual specific phosphatase 9. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Dual specific phosphatase 9 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 Dual specific phosphatase 9 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 Dual specific phosphatase 9, ultimately modulating the amount of Dual specific phosphatase 9 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Dual specific phosphatase 9. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Dual specific phosphatase 9” encompass DNA encoding Dual specific phosphatase 9, 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 Dual specific phosphatase 9. 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 m

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