Antisense modulation of raidd expression

Details Antisense modulation of raidd expression Antisense modulation of raidd expression

2000-11-01

2003-04-22

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, C435S377000, C536S024100, C536S024500, C536S023100, C514S04400A

Reexamination Certificate

active

06551826

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of RAIDD. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding RAIDD. Such compounds have been shown to modulate the expression of RAIDD.
BACKGROUND OF THE INVENTION
Apoptosis, or programmed cell death, is a naturally occurring process that has been strongly conserved during evolution to prevent uncontrolled cell proliferation. This form of cell suicide plays a crucial role in ensuring the development and maintenance of multicellular organisms by eliminating superfluous or unwanted cells. However, if this process goes awry becoming overstimulated, cell loss and degenerative disorders including neurological disorders such as Alzheimers, Parkinsons, ALS, retinitis pigmentosa and blood cell disorders can result. Stimuli which can trigger apoptosis include growth factors such as tumor necrosis factor (TNF), Fas and transforming growth factor beta (TGF&bgr;), neurotransmitters, growth factor withdrawal, loss of extracellular matrix attachment and extreme fluctuations in intracellular calcium levels (Afford and Randhawa,
Mol. Pathol.,
2000, 53, 55-63).
Alternatively, insufficient apoptosis, triggered by growth factors, extracellular matrix changes, CD40 ligand, viral gene products neutral amino acids, zinc, estrogen and androgens, can contribute to the development of cancer, autoimmune disorders and viral infections (Afford and Randhawa,
Mol. Pathol.,
2000, 53, 55-63).
Although several stimuli can induce apoptosis, little is known about the intermediate signaling events, including inhibition, that connect the apoptotic signal to a common cell death pathway conserved across many species. Recently, major advances have been made in understanding the signaling pathways mediated by the tumor necrosis factor receptor (TNFR) family which signals apoptosis.
Two cell surface cytokine receptors of the TNFR family, TNFR-1 and CD95 (Fas/APO-1), act as death receptors and a number of binding proteins have been identified which mediate apoptosis through these receptors. The pathways leading from these receptors involve a proteolytic cascade orchestrated by a family of enzymes known as caspases (Thornberry,
British Medical Bulletin,
1997, 53, 478-490).
Caspases activate apoptosis through proteolytic events triggered by one of several described mechanisms; including ligand binding to the cell surface death receptors of either the TNF or NGF receptor families, changes in mitochondrial integrity or chemical induction (Thornberry,
British Medical Bulletin,
1997, 53, 478-490).
To a large extent, caspase, and consequently apoptotic, signaling is mediated by protein-protein interactions between caspases and their adapter molecules (Cohen,
Biochemistry Journal,
1997, 326, 1-16). These interactions have been localized to three independently folding interaction domains known as the death domain (DD), the death effector domain (DED) and the caspase recruitment domain (CARD) (Hofmann,
Cell. Mol. Life Sci.,
1999, 55, 1113-1128).
RAIDD (also known as CRADD for CASP2 and RIPK1 domain containing Adaptor with Death Domain) is an adaptor molecule which contains both DD and CARD domains. It has been shown to interact with caspase-2 via the CARD domains found in each and with RIP, a serine/threonine kinase, via the respective DD domains. Both caspase-2 and RIP subsequently associate with tumor necrosis factor receptor 1 (TNFR-1) through these interactions with RAIDD (Ahmad et al.,
Cancer Res.,
1997, 57, 615-619; Duan and Dixit,
Nature,
1997, 385, 86-89).
Characterization of the localization of the RAIDD protein revealed that the mRNA is found in various tissues and that expression occurs in most adult tissues and in fetal liver. The highest expression was observed in the thymus, testes and fetal liver (Ahmad et al.,
Cancer Res.,
1997, 57, 615-619). The protein is found predominantly in the cytoplasm and to some extent in the nucleus (Shearwin-whyatt et al.,
Cell Death Differ.,
2000, 7, 155-165). This localization was not found to be affected by TNF-treatment in HeLa or 293T cells.
Overexpression of RAIDD has been shown to induce apoptosis in mammalian cells including human embryonic kidney cells and a breast carcinoma cell line, MCF-7 (Ahmad et al.,
Cancer Res.,
1997, 57, 615-619; Duan and Dixit,
Nature,
1997, 385, 86-89). Overexpression of the CARD domain of RAIDD has been shown to induce the formation of filamentous structures due to CARD-mediated oligomerization (Shearwin-Whyatt et al.,
Cell Death Differ.,
2000, 7, 155-165). This type of complex formation has been previously shown to occur with the overexpression of other death domains. Consequently, the pharmacological modulation of RAIDD activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in pathological conditions involving the aberrant modulation of apoptosis.
Recently, the human and mouse RAIDD genes have been mapped to chromosomes 12 and 10, respectively (Horvat and Medrano,
Genomics,
1998, 54, 159-164). This region contains the putative site for the hg (high growth) gene of the mouse. The hg gene produces an increase in weight gain of up to 50% in homozygous individuals with no concomittant increase in obesity. Using exon trapping studies, Horvat et al. suggest that RAIDD might actually encode the hg gene of the mouse (Horvat and Medrano,
Genomics,
1998, 54, 159-164). The results of these studies suggest that RAIDD may be an attractive therapeutic target for growth or metabolic disorders.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of RAIDD and to date, investigative strategies aimed at modulating RAIDD function have involved the use of antibodies and truncated forms of the protein containing the death domains. Consequently, there remains a long felt need for agents capable of effectively inhibiting RAIDD 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 RAIDD expression.
The present invention provides compositions and methods for modulating RAIDD expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding RAIDD, and which modulate the expression of RAIDD. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of RAIDD 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 RAIDD 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 RAIDD, ultimately modulating the amount of RAIDD produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding RAIDD. As used herein, the terms “target nucleic acid” and “nucleic acid encoding RAIDD” encompass DNA encoding RAIDD, 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”

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