Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-10-06
2002-06-04
Wang, Andrew (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S375000, C536S023100, C536S024500
Reexamination Certificate
active
06399297
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of tumor necrosis factor receptor-associated factors (TRAFs). In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human TRAFs. Such oligonucleotides have been shown to modulate the expression of TRAFs.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) receptor superfamily members regulate cellular proliferation,. differentiation and apoptosis in inflammatory and immune responses. This receptor superfamily comprises a group of related cell-surface receptors including, but not limited to, types 1 and 2 TNF receptors (TNFR1 and TNFR2), Fas, CD27, 4-1BB, CD40 and CD30. Signaling through TNF receptor superfamily members is initiated by oligomerization of the receptors with trimeric ligands, bringing intracellular domains in close proximity (Pullen et al.,
Biochemistry
1998, 37, 11836-11845). Two families of adaptor proteins that associate with TNF receptor superfamily members have been identified: the TNF receptor-associated factor (TRAF) family, and the death domain-containing protein family.
Members of the TRAF family of proteins share an amino-terminal RING finger motif and a homologous carboxy-terminal region, referred to in the art as the TRAF domain (Yuan, J.,
Curr. Opin. Cell Biol
. 1997, 9, 247-251. This conserved carboxy-terminal region binds to receptor cytoplasmic domains and mediates interactions with the signaling proteins NF-&kgr;B inducing kinase (NIK) and I-TRAFT/TANK (Cheng et al.,
Science
1995, 267, 1494-1498; Cheng, G. and Baltimore, D.,
Genes Dev
. 1996, 10, 963-973; Rothe et al.,
Proc. Natl Acad. Sci. USA
1996, 93, 8241-8246; Malinin et al.,
Nature
1997, 385, 540-544). A predicted coiled-coil region mediating TRAF homo- and hetero-oligomerization is in a less conserved region N-terminal to the TRAF domain (Cao et al.,
Nature
1996, 383, 443-446; Cheng et al.,
Science
1995, 267, 1494-1498; Rothe et al.,
Cell
1994, 78, 681-692; Sato et al.,
FEBS Lett
1995, 358, 113-118; and Takeuchi et al.,
J. Biol. Chem
1996, 271, 19935-19942).
The mammalian TRAF family currently includes six members, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5 and TRAF-6. These proteins have generally been found within the cytosols of cells, either in association with cytosolic vesicles or at the plasma membrane after addition of selected TNF family cytokines to the cells. Members of the TRAF family mediate signals for various different receptors. Subsets of TRAF family members have been shown to interact with the TNF receptor family members (TNFR2, CD40, CD30, LT&bgr;R, ATAR, OX40 and 4-1BB).
For example, TRAF-1 and TRAF-2 were identified by their ability to interact with the cytoplasmic domains of TNFR2 (Rothe et al.,
Cell
1994, 78, 681-691). TNFR2 has been associated with TNF's ability to stimulate cell proliferation and activation of NF&kgr;B (Tartaglia et al.,
Proc. Natl Acad. Sci. USA
1991, 88, 9292-9296). TRAF-1 is believed to be involved in the regulation of apoptosis (Speiser et al.,
J. Exp. Med
. 1997, 185, 1777-1783). Depletion of TRAF-2 and its co-associated proteins has also been shown to increase the sensitivity of the cell to undergo apoptosis during activation of death inducing receptors such as TNFR1 (Duckett, C. S. and Thompson, C. B.,
Genes
&
Development
1997, 11, 2810-2821; Yeh et al.,
Immunity
1997, 7, 715-725). Accordingly, the rate of receptor-mediated TRAF-2 consumption and TRAF-2 translation has been suggested to play a dynamic role in the regulation of cell survival (Duckett, C. S. and Thompson, C. B.,
Genes
&
Development
1997, 11, 2810-2821). Targeted disruption of the TRAF-2 gene in mice has also been shown to generate severe defects in c-Jun N-terminal kinase (JNK) activation through TNFR1 (Yeh et al.,
Immunity
1997, 7, 715-725).
TRAF-2 (Rothe et al.,
Science
1995, 269, 1424-1427), TRAF-3 (Cheng et al.,
Science
1995, 267, 1494-1498), TRAF-5 (Ishida et al.,
Proc. Natl Acad. Sci USA
1996, 93, 9437-9442) and TRAF-6 (Pullen et al.,
Biochemistry
1998, 37, 11836-11845) have also been shown to interact with the B lymphocyte receptor CD40. CD40 is a TNF receptor superfamily member that provides activation signals in antigen presenting cells such as B cells, macrophages and dendritic cells. Activation of CD40 leads to B-cell survival, growth and differentiation. In 293T cells, expression of TRAF-3 suppressed constitutive activity of NF&kgr;B, whereas expression of TRAF-5 induced NF&kgr;B activity. Targeted disruption of the TRAF-3 gene in mice causes impaired immune responses to T-dependent antigens and results in early postnatal lethality (Xu et al.,
Immunity
1996, 5, 407-415). TRAF-2, TRAF-5 or TRAF-6 overexpression in mammalian cells also induces JNK activation.
TRAF-4 is expressed in breast cancers. In in vitro binding assays, TRAF-4 has been shown to interact with the cytosolic domain of the lymphotoxin-&bgr; receptor (LT&bgr;R) and weakly with the p75 nerve growth factor receptor but not with TNFR1, TNFR2, Fas or CD40 (Karjewska et al.,
Am. J. of Pathol
. 1998, 152, 6, 1549-1561).
TRAF-6 has also been reported to mediate the signal transduction pathway induced by IL-1 to activate NF&kgr;B by recruiting IL-1 receptor associated kinase (IRAK), a serine/threonine kinase (Cao et al.,
Nature
1996 93:9437-9442). Thus, the role of TRAFs extends beyond being signal transducers for the TNF-receptor superfamily.
The TRAF-5 protein and DNA encoding TRAF-5 are disclosed in WO97/38099. Also disclosed in WO97/38099 is an antisense oligonucleotide against the DNA, an anti-TRAF-5 antibody, a vector containing the DNA, transformants containing this vector and methods of producing TRAF-5 with this vector. In addition, this PCT application discloses methods of screening substances binding to TRAF-5 and substances regulating the activity and expression of this protein.
A TRAF family molecule, a polynucleotide coding for this molecule, an antibody against the molecule and an antisense polynucleotide of the molecule are also disclosed in WO97/31110. Disclosed in this PCT application are the base sequence of the gene and the amino acid of this “unknown” TRAF family molecule, which in addition to the antibody, are suggested to provide means for elucidating the functions of the proteins and the signal transducer system of a TNF-R family in which this molecule participates, to provide probes for research and diagnosis, and to indicate applications for therapeutic agents.
Currently, however, there are no known therapeutic agents which effectively inhibit the synthesis of one or more selected TRAF family members. Consequently, there is a long-felt need for agents capable of effectively inhibiting TRAF expression. Antisense oligonucleotides against one or more TRAFs 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 a selected tumor necrosis factor receptor-associated factor (TRAF), and which modulate the expression of the selected TRAF. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of TRAFs 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 a selected TRAF 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 fun
Baker Brenda F.
Cowsert Lex M.
Monia Brett P.
Xu Xaoxing S.
ISIS Pharmaceuticals Inc.
Licata & Tyrrell P.C.
Wang Andrew
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