Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2000-09-07
2003-01-07
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C436S006000, C436S169000, C436S169000, C536S023100, C536S024100, C536S024500, C514S04400A
Reexamination Certificate
active
06503754
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of BH3 Interacting domain Death agonist. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding BH3 Interacting domain Death agonist. Such compounds have been shown to modulate the expression of BH3 Interacting domain Death agonist.
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 the development and maintenance of multicellular organisms by eliminating superfluous or unwanted cells. However, if this process goes awry, excessive apoptosis results in cell loss and degenerative disorders including neurological disorders such as Alzheimers, Parkinsons, ALS, retinitis pigmentosa and blood cell disorders, while insufficient apoptosis contributes to the development of cancer, autoimmune disorders and viral infections (Thompson,
Science,
1995, 267, 1456-1462).
The Bcl-2 family of proteins, which includes both positive and negative regulators of apoptosis, act as checkpoints upstream of activated protease cascades orchestrated by caspases and are required for all aspects of cell death (Chao and Korsmeyer,
Annu. Rev. Immunol.,
1998, 16, 395-419; Kelekar and Thompson,
Trends Cell Biol.,
1998, 8, 324-330). The Bcl-2 proteins share conserved regions of homology known as Bcl-2 homology domains or BH domains, four of which have been identified to date. It is through the interaction, via dimerization with other Bcl-2 members, of one or more of these domains that the family members exert their pro- or anti-apoptotic effects (Chao and Korsmeyer,
Annu. Rev. Immunol.,
1998, 16, 395-419; Kelekar and Thompson,
Trends Cell Biol.,
1998, 8, 324-330).
Anti-apoptotic members of the family include Bcl-2, Bcl-x
S
, Bcl-x
L
and Bcl-w while pro-apoptotic Bcl-2 members include Bax, Bik, Bid, Bim, Hrk and Blk (Kelekar and Thompson,
Trends Cell Biol.,
1998, 8, 324-330). Three of the pro-apoptotic proteins, Bad, Bid, and Bim, show little similarity to Bcl-2, containing only one BH3 domain (Kelekar and Thompson,
Trends Cell Biol.,
1998, 8, 324-330). Disclosed in the PCT application WO 99/16787 are the polypeptide and polynucleotide sequence of the BH3 domain found in Bcl-2 family members, specifically BID, and methods to promote apoptosis in a cell by administering an effective amount of the BH3 domain peptide (Korsmeyer, 1999).
Bid (also known as BID or BH3 Interacting domain Death agonist) is a member of the Bcl-2 family and has been shown to dimerize with either Bcl-2, a cell death antagonist, or Bax, a cell death agonist, and can be found in both cytosolic and membrane fractions (Wang et al.,
Genes Dev.,
1996, 10, 2859-2869).
Upon cell surface signaling by a death receptor, it is known that BH3 Interacting domain Death agonist is cleaved by caspase 8 and the C-terminus translocates to the mitochodria and triggers cytochrome c release (Gross et al.,
J. Biol. Chem.,
1999, 274, 1156-1163). It is now known that this process is mediated by the binding of BH3 Interacting domain Death agonist to Bax, with the concomitant induction of a structural change in Bax (Desagher et al.,
J. Cell. Biol.,
1999, 144, 891-901) and is diminished by binding to Bcl-2 (Luo et al.,
Cell,
1998, 94, 481-490).
Due to the integral role played by BH3 Interacting domain Death agonist in apoptosis, the pharmacological modulation of BH3 Interacting domain Death agonist activity and/or expression may therefore be an appropriate point of therapeutic intervention in pathological conditions involving deregulated cell death. Disclosed in the PCT publication, WO 00/11162 is a novel form of BH3 Interacting domain Death agonist (p15 BID) created by the selective cleavage of the cytosolic BH3 Interacting domain Death agonist protein. This 15kD polypeptide, once cleaved, translocates to the mitochondria where it resides as an integral membrane protein and is required for the release of cytochrome c (Gross and Korsmeyer, 2000). Also disclosed are uses of p15 BID and mutant p15 BID polypeptides for the modulation of apoptosis.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of BH3 Interacting domain Death agonist and to date, investigative strategies aimed at modulating BH3 Interacting domain Death agonist function have involved the use of antibodies, molecules that block upstream entities such as caspase inhibitors (Sun et al.,
J. Biol. Chem.,
1999, 274, 5053-5060) and gene knock-outs in mice (Yin et al.,
Nature,
1999, 400, 886-891).
Disclosed in U.S. Pat. No. 5,955,593 and the PCT application WO 98/09980 are the peptide and nucleic acid sequence of human BH3 Interacting domain Death agonist as well as antibodies, vectors and host cells used to express the BH3 Interacting domain Death agonist protein and reporter constructs used to detect said expression (Korsmeyer, 1999; Korsmeyer, 1998). Antisense oligonucleotides complementary to BH3 Interacting domain Death agonist 15 to 30 nucleotides are also generally disclosed as are methods for treating a disease condition comprising administration of an inhibitory effective amount of purified BH3 Interacting domain Death agonist antisense polynucleotide (Korsmeyer, 1998).
Disclosed in U.S. Pat. No. 5,998,583 are BH3 Interacting domain Death agonist polypeptide and nucleotide derivatives and compositions and uses thereof (Korsmeyer, 1999). there remains, however, a long felt need for additional agents capable of effectively inhibiting BH3 Interacting domain Death agonist 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 BH3 Interacting domain Death agonist expression.
The present invention provides compositions and methods for modulating BH3 Interacting domain Death agonist expression, including modulation of the cleavable form of BH3 Interacting domain Death agonist, p15 BID.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding BH3 Interacting domain Death agonist, and which modulate the expression of BH3 Interacting domain Death agonist. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of BH3 Interacting domain Death agonist 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 BH3 Interacting domain Death agonist 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 BH3 Interacting domain Death agonist, ultimately modulating the amount of BH3 Interacting domain Death agonist produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding BH3 Interacting domain Death agonist. As used herein, the terms “target nucleic acid” and “nucleic acid encoding BH3 Interacting domain Death agonist” encompass DNA encoding BH3 Interacting domain Death agonist, 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 norma
Wyatt Jacqueline
Zhang Hong
ISIS Pharmaceuticals Inc.
Licata & Tyrrell P.C.
McGarry Sean
LandOfFree
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