Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-07-27
2002-05-28
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, C435S455000, C536S023100, C536S024300, C536S024310, C536S024330, C536S024500
Reexamination Certificate
active
06395545
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Inhibitor-kappa B Kinase-alpha. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human Inhibitor-kappa B Kinase-alpha. Such oligonucleotides have been shown to modulate the expression of Inhibitor-kappa B Kinase-alpha.
BACKGROUND OF THE INVENTION
Inflammation is a localized protective response mounted by tissues in response to injury, infection, or tissue destruction resulting in the destruction of the infectious or injurious agent and isolation of the injured tissue. A typical inflammatory response proceeds as follows: recognition of an antigen as foreign or recognition of tissue damage, synthesis and release of soluble inflammatory mediators, recruitment of inflammatory cells to the site of infection or tissue damage, destruction and removal of the invading organism or damaged tissue, and deactivation of the system once the invading organism or damage has been resolved. In many human diseases with an inflammatory component, the normal, homeostatic mechanisms which attenuate the inflammatory responses are defective, resulting in damage and destruction of normal tissue. Consequently, much effort has been made to identify the molecular mechanisms underlying regulation of inflammatory responses.
For example, both TNF-alpha and IL-1 have been identified as important extracellular mediators that induce expression of a number of gene products involved in tissue inflammation (DiDonato et al.,
Nature,
1997, 388, 548-554). Although IL-1 and TNF-alpha bind to distinct cell surface receptors, it is currently believed that their intracellular signals ultimately converge to induce a similar spectrum of gene products through activation of the nuclear transcription factor NF-kappa-B (DiDonato et al.,
Nature,
1997, 388, 548-554). For several years, it has been known that NF-kappa-B normally exists in the cytoplasm bound to a family of inhibitor proteins known as IKB-alpha (Inhibitor-Kappa-B-alpha) and IKB-beta. Phosphorylation of the IKB's triggers them to be ubiquitinated and then degraded, thereby releasing NF-kappa-B, which is then free to translocate to the nucleus and activate expression of its downstream targets. Recently, two closely related kinases responsible for IKB phosphorylation (and hence NF-kappa-B activation) have been identified and are termed Inhibitor-Kappa B Kinase-alpha (IKK-l, for I-Kappa-B Kinase 1) and Inhibitor-Kappa B Kinase-beta (IKK-2, for I-Kappa-B Kinase 2) (DiDonato et al.,
Nature,
1997, 388, 548-554; Zandi et al.,
Science,
1998, 281, 1360-1363; Zandi et al.,
Cell,
1997, 91, 243-252). In these studies, Inhibitor-Kappa B Kinase-alpha and Inhibitor-Kappa B Kinase-beta were found to directly phosphorylate IKB-alpha and IKB-beta. Further, transfection of HeLa cells with an expression vector containing the Inhibitor-Kappa B Kinase-alpha gene in antisense orientation was found to inhibit induction of NF-kappa-B activity by TNF-alpha and interleukin-1.
It is currently believed that Inhibitor-Kappa B Kinase-alpha and/or Inhibitor-Kappa B Kinase-beta may represent the point at which the signal transduction pathways activated by TNF-alpha and IL-1 converge to generate active NF-kappa-B (DiDonato et al.,
Nature,
1997, 388, 548-554). It has therefore been proposed that inhibition of Inhibitor-Kappa B Kinase-alpha or Inhibitor-Kappa B Kinase-beta may represent a method to uniformly inhibit the diverse range of molecular signals that lead to activation of the inflammatory response (Israel,
Nature,
1997, 388, 519-521). Recently, activation of Inhibitor-Kappa B Kinase-alpha and Inhibitor-Kappa B Kinase-beta by the HTLV-1 protein Tax was demonstrated (Geleziunas et al.,
Mol. Cell. Biol.,
1998, 18, 5157-5165). Since activation of NF-kappa-B in HTLV infected T-cells has been implicated in the development of T-cell leukemia, it has been proposed that activation of Inhibitor-Kappa B Kinase-alpha and/or Inhibitor-Kappa B Kinase-beta through Tax may play a role in T-cell leukemia tumorigenesis as well (Geleziunas et al.,
Mol. Cell. Biol.,
1998, 18, 5157-5165).
As a result of the role that Inhibitor-Kappa B Kinase-alpha activation is believed to play in the development of T-cell leukemia and in the activation of the inflammatory responses, there is a great desire to provide compositions of matter which can modulate the expression of Inhibitor-Kappa B Kinase-alpha.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Inhibitor-Kappa B Kinase-alpha. Consequently, there is a long-felt need for agents capable of effectively inhibiting Inhibitor-Kappa B Kinase-alpha. It is anticipated that oligonucleotides capable of modulating the expression of Inhibitor-Kappa B Kinase-alpha may provide for a novel class of agents with activity towards a variety of inflammatory disorders or diseases with an inflammatory component such as asthma, juvenile diabetes mellitus, myasthenia gravis, Graves' disease, rheumatoid arthritis, allograft rejection, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus erythematosus, systemic lupus erythematosus, diabetes, multiple sclerosis, contact dermatitis, rhinitis and various allergies, or hyperproliferative disorders such as leukemias and other tumors. Antisense oligonucleotides against Inhibitor-Kappa B Kinase-alpha may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding Inhibitor-kappa B Kinase-alpha, and which modulate the expression of Inhibitor-kappa B Kinase-alpha. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of Inhibitor-kappa B Kinase-alpha 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 Inhibitor-kappa B Kinase-alpha 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 Inhibitor-kappa B Kinase-alpha, ultimately modulating the amount of Inhibitor-kappa B Kinase-alpha produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Inhibitor-kappa B Kinase-alpha. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Inhibitor-kappa B Kinase-alpha” encompass DNA encoding Inhibitor-kappa B Kinase-alpha, 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 Inhibitor-kappa B Kinase-alpha. In the
Cowsert Lex M.
Monia Brett P.
Epps Janet L.
Isis Pharmaceuticals , Inc.
Licata & Tyrrell P.C.
McGarry Sean
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