Antisense inhibition of rank expression

Details Antisense inhibition of rank expression Antisense inhibition of rank expression

1999-11-05

2001-01-09

Elliott, George C. (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S006120, C435S091100, C435S091500, C435S325000, C435S455000, C536S023100, C536S024500, C536S025300

Reexamination Certificate

active

06171860

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of RANK. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human RANK. Such oligonucleotides have been shown to modulate the expression of RANK.
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, and CD30. Signaling through TNF receptor superfamily members is initiated by oligomerization of the receptors with trimeric ligands, bringing intracellular domains in close proximity (Baker and Reddy,
Oncogene,
1998, 17, 3261-3270). These receptors are devoid of any intrinsic catalytic activity and therefore must recruit a variety of adaptor proteins to the cytoplasmic domain in order to relay the signals that eventually reach the nucleus. 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.
The mammalian TRAF family currently includes six members and 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. TRAF family members have been shown to interact with and mediate signal from various subsets of TNF receptors. One such receptor, recently identified in dendritic cells and shown to enhance T-cell growth and dendritic cell function, is RANK (Receptor Activator of Nuclear Factor-kappa B) (Anderson et al.,
Nature,
1997, 390, 175-179; Green and Flavell,
J. Exp. Med.,
1999, 189, 1017-1020).
The nucleic acid and polypeptide sequences of human RANK are disclosed in the PCT publication WO 98/28424 as are antibodies to the RANK polypeptide, expression systems comprising vectors and host cells transformed with vectors encoding RANK and methods to regulate an immune or inflammatory response by treating an individual with soluble RANK polypeptide compositions. Sense and antisense oligonucleotides that hybridize to RANK DNA or mRNA are also generally disclosed (Anderson et al., 1998).
Signaling through RANK has been shown to activate both the NF-kappa-B pathway as well as the Jun N-terminal Kinase (JNK) pathway, and both occur via interactions with TRAF family proteins (Darnay et al.,
J. Biol. Chem.,
1998, 273, 20551-20555).
NF-kappa-B proteins are involved in a diverse set of signaling pathways involving the immune response, apoptosis, cancer and growth. RANK has been shown to activate the NF-kappa-B pathway through its interaction with TRAF-2, 5 and 6 and another kinase, NF-kappa-B inducing kinase (NIK) (Darnay et al.,
J. Biol. Chem.,
1999, 274, 7724-7731; Galibert et al.,
J. Biol. Chem.,
1998, 273, 34120-34127; Wong et al.,
J. Biol. Chem.,
1998, 273, 28355-28359).
Alternatively, interactions between RANK and TRAF-1, 2, 3, and 6 were shown to activate the JNK pathway (Kim et al.,
FEBS Lett.,
1999, 443, 297-302). This pathway was originally identified as an oncogene- and ultraviolet light-stimulated kinase pathway but is now known to be activated by growth factors, cytokines and T-cell costimulation. The involvement of RANK with the JNK pathway has major implications for the role of RANK in multiple pathologic conditions, especially those initiated by cellular stressors such as cancer, and inflammatory responses.
More recently it has been demonstrated that RANK is essential to signaling pathways involved in bone morphogenesis, more specifically, osteoclastogenesis or the process of osteoclast differentiation (Nakagawa et al.,
Biochem. Biophys. Res. Commun.,
1998, 253, 395-400). In these and other studies RANK was shown to be the receptor for osteoclast differentiation factor (ODF) and to mediate osteoclast differentiation, activation and, in some cases, osteoclast function (Hsu et al.,
Proc. Natl. Acad. Sci. U. S. A.,
1999, 96, 3540-3545; Jimi et al.,
J. Immunol.,
1999, 163, 434-442; Nakagawa et al.,
Biochem. Biophys. Res. Commun.,
1998, 253, 395-400). These studies suggest that proper signaling through RANK is critical to the regulated homeostasis that must be maintained between the processes of bone formation by osteoblasts and bone resorption by osteoclasts.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of RANK and, therefore, the pharmacological modulation of RANK expression and/or function may be an appropriate point of therapeutic intervention in pathological conditions.
To date, investigative strategies aimed at modulating RANK function have involved the use of antibodies and strategies that block ligand-receptor interactions, such as the use of soluble receptors. However, these strategies are untested as therapeutic protocols and consequently, there remains a long felt need for additional agents capable of effectively inhibiting RANK 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 RANK expression. The present invention provides compositions and methods for modulating RANK expression.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding RANK, and which modulate the expression of RANK. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of RANK 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 RANK 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 RANK, ultimately modulating the amount of RANK produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding RANK. As used herein, the terms “target nucleic acid” and “nucleic acid encoding RANK” encompass DNA encoding RANK, 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 RANK. 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

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