Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-04-27
2002-06-25
LeGuyader, John L. (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S006120, C435S091100, C435S325000, C435S366000, C536S023100, C536S024310, C536S024330, C536S024500
Reexamination Certificate
active
06410324
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of Tumor Necrosis Factor Receptor 2. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding Tumor Necrosis Factor Receptor 2. Such compounds have been shown to modulate the expression of Tumor Necrosis Factor Receptor 2.
BACKGROUND OF THE INVENTION
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals into intracellular signals that in turn modulate biochemical pathways. Examples of such extracellular signaling molecules include growth factors, cytokines, and chemokines. The cell surface receptors of these molecules and their associated signal transduction pathways are therefore one of the principal means by which cellular behavior is regulated. 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 signal transduction pathways.
For example, the polypeptide cytokine tumor necrosis factor (TNF) is normally produced during infection, injury, or invasion where it serves as a pivotal mediator of the inflammatory response. In recent years, a number of in vivo animal and human studies have demonstrated that overexpression TNF by the host in response to disease and infection is itself responsible for the pathological consequences associated with the underlying disease. For example, septic shock as a result of massive bacterial infection has been attributed to infection-induced expression of TNF. Thus, systemic exposure to TNF at levels comparable to those following massive bacterial infection has been shown to result in a spectrum of symptoms (shock, tissue injury, capillary leakage, hypoxia, pulmonary edema, multiple organ failure, and high mortality rate) that is virtually indistinguishable from septic shock syndrome (Tracey and Cerami,
Annu. Rev. Med.,
1994, 45, 491-503). Further evidence has been provided in animal models of septic shock, in which it has been demonstrated that systemic exposure to anti-TNF neutralizing antibodies block bacterial-induced sepsis (Tracey and Cerami,
Annu. Rev. Med.,
1994, 45, 491-503). In addition to these acute effects, chronic exposure to low-dose TNF, results in a syndrome of cachexia marked by anorexia, weight loss, dehydration, and depletion of whole-body protein and lipid. Chronic production of TNF has been implicated in a number of diseases including AIDS and cancer (Tracey and Cerami,
Annu. Rev. Med.,
1994, 45, 491-503). To date, two distinct TNF cells surface receptors, known as Tumor necrosis factor receptor 1 and Tumor necrosis factor receptor 2, have been described. Molecular analysis of Tumor necrosis factor receptor 1 and Tumor necrosis factor receptor 2 have shown that the two receptors share little homology in their intracellular domains and appear to activate distinct intracellular pathways (Tracey and Cerami,
Annu. Rev. Med.,
1994, 45, 491-503).
Tumor necrosis factor (TNFR2, also known as CD120b, p75 TNFR and TNFR-beta receptor) was first cloned in 1990 (Schall et al.,
Cell,
1990, 61, 361-370.) and mapped to chromosomal locus 1p36.2 in 1996 (Beltinger et al.,
Genomics,
1996, 35, 94-100).
Bruce et al. used targeted gene expression to generate mice lacking both TNFRs and concluded that drugs which target the TNF signaling pathways may prove beneficial in treating stroke or traumatic brain injury (Bruce et al.,
Nat. Med.,
1996, 2, 788-794.). Tumor necrosis factor receptor 2 knockout mice were also used to establish a crucial role for Tumor necrosis factor receptor 2 in experimental cerebral malaria (Lucas et al.,
Eur. J. Immunol.,
1997, 27, 1719-1725) and autoimmune encephalomyelitis (Suvannavejh et al.,
Cell Immunol.,
2000, 205, 24-33), models for human cerebral malaria and multiple sclerosis, respectively.
Agostini et al. have determined that Tumor necrosis factor receptor 2 is present at high density on T cells and may play a role in the immune regulatory mechanisms that lead to alveolitis in the pulmonary microenvironment of interstitial lung disease (Agostini et al.,
Am. J. Respir. Crit. Care Med.,
1996, 153, 1359-1367). Tumor necrosis factor receptor 2 is implicated in human metabolic disorders of lipid metabolism and associated with obesity and insulin resistance (Fernandez-Real et al.,
Diabetes Care,
2000, 23, 831-837), familial combined hyperlipidemia (Geurts et al.,
Hum. Mol. Genet.,
2000, 9, 2067-2074.; van Greevenbroek et al.,
Atherosclerosis,
2000, 153, 1-8), hypertension and hypercholesterolemia (Glenn et al.,
Hum. Mol. Genet.,
2000, 9, 1943-1949). Tumor necrosis factor receptor 2 has also recently been associated with human narcolepsy (Komata et al.,
Tissue Antigens,
1999, 53, 527-533). In addition, Tumor necrosis factor receptor 2 polymorphism appears to lead to susceptibility to systemic lupus erythematosus (Hohjoh et al.,
Tissue Antigens,
2000, 56, 446-448).
An antisense oligonucelotide targeting the initiation site of the human Tumor necrosis factor receptor 2 gene was used to inhibit Tumor necrosis factor receptor 2 expression in a human neuronal cell line (Shen et al.,
J. Biol. Chem.,
1997, 272, 3550-3553).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Tumor necrosis factor receptor 2 and investigative strategies aimed at modulating Tumor necrosis factor receptor 2 function have involved the use of inhibitors such as antibodies and antisense oligonucleotides.
Antisense technology is emerging as an effective means of reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic and research applications involving modulation of Tumor necrosis factor receptor 2 expression.
The present invention provides compositions and methods for modulating the expression of Tumor necrosis factor receptor 2.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding Tumor Necrosis Factor Receptor 2, and which modulate the expression of Tumor Necrosis Factor Receptor 2. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of Tumor Necrosis Factor Receptor 2 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 Tumor Necrosis Factor Receptor 2 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 Tumor Necrosis Factor Receptor 2, ultimately modulating the amount of Tumor Necrosis Factor Receptor 2 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Tumor Necrosis Factor Receptor 2. As used herein, the terms “target nucleic acid” and “nucleic acid encoding Tumor Necrosis Factor Receptor 2” encompass DNA encoding Tumor Necrosis Factor Receptor 2, 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 “ant
Bennett C. Frank
Watt Andrew T.
LeGuyader John L.
Licata & Tyrell P.C.
Schmidt M
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