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
2002-10-22
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
06468796
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of bifunctional apoptosis regulator. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding bifunctional apoptosis regulator. Such compounds have been shown to modulate the expression of bifunctional apoptosis regulator.
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). Consequently, apoptosis is regulated under normal circumstances by the interaction of gene products that either induce or inhibit cell death and several gene products which modulate the apoptotic process have now been identified.
There are two major pathways for induction of apoptosis: intrinsic and extrinsic (Ashkenazi and Dixit,
Science
, 1998, 281, 1305-1308; Salvesen and Dixit,
Cell
, 1997, 91, 443-446; zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602). The extrinsic pathway is represented by the tumor necrosis factor family of receptors which utilize protein interaction modules known as death domains and death effector domains (DEDs) to assemble receptor signaling complexes that recruit and activate certain caspase family cell death proteases (Ashkenazi and Dixit,
Science
, 1998, 281, 1305-1308; Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602). The intrinsic pathway involves the participation mitochondria which release caspase-activation proteins (Green and Reed,
Science
, 1998, 281, 1309-1312; Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602). The Bcl-2 family of anti-apoptotic proteins is involved in regulation of this mitochondria-dependent apoptosis pathway (Green and Reed,
Science
, 1998, 281, 1309-1312; Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602).
Bifunctional apoptosis regulator (BAR) is a recently discovered protein with a DED-like domain and a Bcl-2 regulatory domain (Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602). Zhang et al. suggest that bifunctional apoptosis regulator's multidomain structure may serve as a scaffold protein that integrates interactions and communication between the DED-containing initiator caspases of the extrinsic apoptosis pathway and Bcl-2 family proteins of the intrinsic apoptosis pathway (Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602).
Deregulation of apoptosis has been implicated in autoimmune disease, acquired immune deficiency syndrome, and other viral (and bacterial) infections, as well as in neurodegenerative disorders and cancer. Furthermore, deregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis and atherosclerosis and perhaps on the process of aging itself (Fadeel et al.,
Biochem. Biophys. Res. Commun
., 1999, 266, 699-717).
Strategies aimed at modulating bifunctional apoptosis regulator function have been so far limited to the use of antibodies (Zhang et al.,
Proc. Natl. Acad. Sci. USA
, 2000, 97, 2597-2602) and are as yet untested as therapeutic protocols. Consequently there remains a long felt need for agents capable of effectively inhibiting bifunctional apoptosis regulator 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 bifunctional apoptosis regulator expression.
The present invention provides compositions and methods for modulating bifunctional apoptosis regulator expression.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding bifunctional apoptosis regulator, and which modulate the expression of bifunctional apoptosis regulator. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of bifunctional apoptosis regulator 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 bifunctional apoptosis regulator 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 bifunctional apoptosis regulator, ultimately modulating the amount of bifunctional apoptosis regulator produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding bifunctional apoptosis regulator. As used herein, the terms “target nucleic acid” and “nucleic acid encoding bifunctional apoptosis regulator” encompass DNA encoding bifunctional apoptosis regulator, 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 bifunctional apoptosis regulator. 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 expression and mRNA is a preferred target.
It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention
ISIS Pharmaceuticals Inc.
LeGuyader John L.
Licata & Tyrrell P.C.
Schmidt M
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