Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-09-28
2004-02-17
Lacourciere, Karen (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S325000, C435S091100, C435S091300, C435S006120, C536S024500, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06692959
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of IL-1 receptor-associated kinase-4. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding IL-1 receptor-associated kinase-4. Such compounds have been shown to modulate the expression of IL-1 receptor-associated kinase-4.
BACKGROUND OF THE INVENTION
The proinflammatory cytokine interleukin-1 (IL-1) is a central regulator in immune and inflammatory responses, involved in generating systemic and local response to infection, injury, and immunologic challenges. IL-1 is produced mainly by activated macrophages and monocytes, and participates in lymphocyte activation, induction of fever, leukocyte trafficking, the acute phase response, and cartilage remodeling. The expression of more than 90 genes is affected by IL-1, including genes that encode other cytokines, cytokine receptors, acute-phase reactants, growth factors, tissue-remodeling enzymes, extracellular matrix components, and cell adhesion molecules. IL-1 is a critical cytokine in the pathogenesis of viral infections and inflammatory diseases such as rheumatoid arthritis (O'Neill and Greene,
J. Leukoc. Biol.,
1998, 63, 650-657).
Cellular responses are transduced through the type I IL-1 receptor (IL-1RI), located on the plasma membrane of a variety of IL-1-responsive cells. Binding of IL-1 to IL-1RI ultimately triggers activation of transcription factors in the NF-&kgr;B family, which are bound by inhibitory proteins (I&kgr;BS) and remain anchored in the cytoplasm until the inhibitory proteins are degraded. In response to IL-1, tumor necrosis factor (TNF), or other extracellular stimuli such as lipopolysaccharides, double-stranded RNA, or oxidative stress, and once unbound and activated, NF-&kgr;B is then transported to the nucleus, where it influences the activity of many genes (O'Neill and Greene,
J. Leukoc. Biol.,
1998, 63, 650-657).
A family of proteins has been described that share significant homology with the type I IL-1 receptor in their signaling domains. This family includes IL-1 receptor accessory protein (IL1-RAcP), which does not bind IL-1, but is essential for IL-1 signaling; a Drosophila receptor protein, Toll; a number of human Toll-like receptors (hTLRs); the interferon-&ggr;-inducing factor/IL-1&ggr;/IL-18 receptor-related protein (IL-1Rrp), a number of plant proteins, and the IL-1 receptor-associated kinases (IRAK-1, IRAK-2, and IRAK-M). All members of this family appear to be involved in host responses to injury and infection (O'Neill and Greene,
J. Leukoc. Biol.,
1998, 63, 650-657; Wesche et al.,
J. Biol. Chem.,
1999, 274, 19403-19410).
The IL-1 signaling pathway in mammals is analogous to the Toll pathway in
Drosophila melanogaster
. Homologues of the IL-1 receptor-associated kinases are found in
D. melanogaster
(Pelle) and in plants (Pto), and in these systems, the kinases have been shown to be components of a signal transduction system leading to the activation of NF-&kgr;B. A model for the signaling pathway in which IL-1 receptor associated kinase-4 is likely to function is as follows: when cells receive the extracellular IL-1 signal, a complex between IL-1RI and IL-1RAcP is formed (Huang et al.,
Proc. Natl. Acad. Sci. U.S.A.,
1997, 94, 12829-12832), the cytosolic adapter protein MyD88 interacts with IL-1RAcP in the receptor complex (Burns et al.,
J. Biol. Chem.,
1998, 273, 12203-12209), and MyD88 rapidly recruits a IL-1 receptor-associated kinase into the complex. Tollip also interacts with IL-1RAcP and is believed to block autophosphorylation of the IL-1 receptor-associated kinase or its association with another kinase; thus, the association of Tollip with the IL-1 receptor-associated kinase is inhibitory (Burns et al.,
Nat. Cell Biol.,
2000, 2, 346-351). At some point after its IL-1-dependent association with the receptor complex, the IL-1 receptor-associated kinase may be extensively phosphorylated and its own serine/threonine kinase catalytic activity activated (Cao et al.,
Science,
1996, 271, 1128-1131). IL-1 receptor-associated kinase-1 is known to interact with an adapter protein, TRAF6, a protein critical for IL-1-dependent activation of NF-&kgr;B, which then dissociates from the receptor complex. TRAF6 relays a signal via NF-&kgr;B-inducing kinase (NIK) to two I-&kgr;B kinases (IKK-1 and -2), culminating in activation of NF-&kgr;B (Bacher et al.,
FEBS Lett.,
2001, 497, 153-158; Jefferies et al.,
Mol. Cell. Biol.,
2001, 21, 4544-4552; O'Neill and Greene,
J. Leukoc. Biol.,
1998, 63, 650-657).
IL-1 receptor-associated kinase-4 (also known as interleukin 1 receptor-associated kinase 4, IRAK4, IRAK-4, DD-1, and NY-REN-64 antigen) was originally identified as NY-REN-64, one of 65 human tumor antigens recognized by autologous antibodies from patients with renal cell carcinoma using serological analysis of recombinant cDNA expression libraries (SEREX). Sequence analysis of the NY-REN-64 cDNA clone identified in the SEREX screen revealed a novel gene encoding a transcript of 2.8 kilobases and a predicted protein of 460 amino acids (Genbank Accession AF155118) noted to bear a protein kinase motif (Scanlan et al.,
Int. J. Cancer,
1999, 83, 456-464). Based on its homology to the other IL-1 receptor-associated kinases, this gene has more recently been placed in the IRAK family and given the name IL-1 receptor-associated kinase-4.
There is evidence that the IRAKs are functionally redundant in vivo. Members of this family of IL-1 receptor-associated kinases may also have overlapping yet distinct signaling roles. IRAK-2 and IRAK-M can reconstitute the IL-1 response in human embryonic kidney 293 mutant cell lines lacking IRAK-1 (Wesche et al.,
J. Biol. Chem.,
1999, 274, 19403-19410). Furthermore, at least IL-1 receptor-associated kinase-1 plays a role in regulation of multiple signaling pathways. In addition to transducing the IL-1 signal, IL-1 receptor-associated kinase-1 also transduces a signal initiated by binding of tumor necrosis factor (TNF)-&agr; to its receptor, again leading to activation of NF-&kgr;B (Vig et al.,
J. Biol. Chem.,
1999, 274, 13077-13084; Vig et al.,
J. Biol. Chem.,
2001, 276, 7859-7866). In another signal transduction pathway separate from its activation of NF-&kgr;B, IL-1 receptor-associated kinase-1 has also been implicated in activation of the Jun amino-terminal kinase (JNK) and the transcription factor AP-1 (Bacher et al.,
FEBS Lett.,
2001, 497, 153-158).
Disclosed and claimed in PCT Publication WO 00/73801 are methods of diagnosing a disorder and methods for treating a pathological cell condition characterized by aberrant expression of a human cancer associated antigen encoded by a nucleic acid molecule, wherein the nucleic acid molecule is IL-1 receptor-associated kinase-4 or a fragment thereof, and wherein the agent used in said method of treatment is an antisense nucleic acid molecule. Also claimed is an isolated nucleic acid molecule of sufficient length to represent a sequence unique within the human genome, identifying a nucleic acid encoding IL-1 receptor-associated kinase-4. Further claimed is a method for treating a subject having a condition characterized by IL-1 receptor-associated kinase-4 expression (Obata, 2000).
Disclosed and claimed in PCT Publication WO 01/51641 are isolated nucleic acids and expression vector constructs encoding an IL-1 receptor-associated kinase-4 polypeptide as well as isolated polypeptides with at least about 98% amino acid sequence identity to IL-1 receptor-associated kinase-4. Further claimed is a method for identifying a compound useful in the treatment or prevention of inflammatory diseases by expressing IL-1 receptor-associated kinase-4 and truncated or mutant forms of the IL-1 receptor-associated kinase-4 protein. Also claimed is a method of treating an inflammatory disease in a patient by administering a compound that modulates IL-1 receptor-associated kinase-4, as well as a method of inhib
Bennett C. Frank
Freier Susan M.
Isis Pharmaceuticals , Inc.
Lacourciere Karen
Licata & Tyrrell P.C.
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