Antisenses inhibition of SRC-2 expression

Details Antisenses inhibition of SRC-2 expression Antisenses inhibition of SRC-2 expression

2000-11-27

2002-03-12

Wang, Andrew (Department: 1635)

Chemistry: molecular biology and microbiology

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

Method of regulating cell metabolism or physiology

C435S006120, C435S325000, C435S366000, C536S023100, C536S024500, C514S04400A

Reexamination Certificate

active

06355483

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of SRC-2. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human SRC-2. Such oligonucleotides have been shown to modulate the expression of SRC-2.
BACKGROUND OF THE INVENTION
Steroid, thyroid and retinoid hormones produce a diverse array of physiologic effects through the regulation of gene expression. Upon entering the cell, these hormones bind to a unique group of intracellular nuclear receptors which have been characterized as ligand-dependent transcription factors. This complex then moves into the nucleus where the receptor and its cognate ligand interact with the transcription preinitiation complex affecting its stability and ultimately the rate of transcription of the target genes. The interactions of the liganded receptor with the specific elements in the promoter region are mediated by two classes of molecules; corepressors which inhibit transactivation and coactivators which enhance transactivation.
SRC-2 (also known as steroid receptor coactivator-2, TIF2, GRIP-1 and NcoA-2) is a member of the growing family of transcription coactivators.
Characterization studies of SRC-2 demonstrated that the protein could mediate transcriptional transactivation by steroid receptors including the androgen, estrogen and progesterone receptors (Voegel et al.,
Embo J.,
1996, 15, 3667-3675) as well as non-steroid receptors which include thyroid, retinoid, gluccocorticoid and Vitamin-D receptors (Voegel et al.,
Embo J.,
1998, 17, 507-519). Furthermore, expression of the transcript was found in most human tissues including the pancreas, skeletal muscle, liver, lung, placenta, brain and heart, with lower levels in the kidney (Voegel et al.,
Embo J.,
1996, 15, 3667-3675).
SRC-2 has recently been implicated in the altered modulation of gene transcription in a distinct subtype of acute myeloid leukemia (Carapeti et al.,
Blood,
1998, 91, 3127-3133). These studies showed that the chromosomal translocation inv(8)(p11q13) resulted in a fusion protein of MOZ (monocytic leukemia zinc finger protein) to SRC-2. The resulting protein retains the acetyltransferase domain of both proteins and therefore is thought to contribute to the disease process through a mechanism involving abnormal histone acetylation.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SRC-2. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting SRC-2 function.
It is anticipated that antisense oligonucleotides against SRC-2 may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the effective and specific modulation of SRC-2 expression.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding SRC-2, and which modulate the expression of SRC-2. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of SRC-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 SRC-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 antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding SRC-2, ultimately modulating the amount of SRC-2 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding SRC-2. As used herein, the terms “target nucleic acid” and “nucleic acid encoding SRC-2” encompass DNA encoding SRC-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 “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 SRC-2. 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, the target is a nucleic acid molecule encoding SRC-2. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding SRC-2, regardless of the sequence(s) of such codons.
It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively). The terms “start codon region” and “translation initiation codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous

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