Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-08-01
2003-03-25
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, C435S091100, C435S325000, C536S023100, C536S023200, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06537811
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of SAP-1. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding SAP-1. Such compounds have been shown to modulate the expression of SAP-1.
BACKGROUND OF THE INVENTION
A principal mechanism of cellular regulation is 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.
Sequence-specific DNA binding proteins, more commonly known as transcription factors, represent a group of molecules within the cell that function to connect extracellular signals to intracellular responses by directly affecting gene transcription. Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind consensus regions in the promoters of various genes and activate the transcription of the respective target gene.
The Ets DNA-binding proteins form a family of at least 45 eukaryotic members that usually bind DNA as heteromeric protein complexes. Proteins within this family are found in species from fruit flies to humans and regulate multiple genes involved in cellular proliferation and differentiation. The proteins function as either transcriptional activators or repressors and their activities are often regulated by signal transduction pathways. The genes encoding Ets proteins are frequent targets for chromosomal translocations resulting in various leukemias (Mo et al.,
Mol. Cell
., 1998, 2, 201-212).
The ternary complex factors (TCFs) are a subgroup of the Ets proteins. TCFs assemble complexes with the ubiquitous MADS-box protein serum-response factor (SRF) to regulate transcription of the immediate early c-fos protooncogene (Wasylyk et al.,
Trends Biochem. Sci
., 1998, 23, 213-216). TCF function is mediated by the cooperative binding of the TCF and SRF proteins to adjacent DNA targets at the serum response element (SRE) of the c-fos promoter region. TCFs share a conserved N-terminal ETS domain, a 20-amino acid region called the B box that mediates interaction with the SRF, and a C-terminal region that serves as a target for phosphorylation by the mitogen activated protein (MAP) kinase for the transactivation of the c-fos gene (Mo et al.,
Mol. Cell
., 1998, 2, 201-212).
SRF accessory protein (also known as SRF accessory protein 1A, ELK4 ETS-domain protein, SRF accessory protein 1, ELK4, SAP1, serum response factor accessory protein 1, ELK-4, and SAP-1), a member of the TCF subgroup, has been cloned (Dalton and Treisman,
Cell
, 1992, 68, 597-612) and mapped to chromosome 1q32 (Shipley et al.,
Genomics
, 1994, 23, 710-711). In 1994, Treisman reported a revised sequence for SAP-1 which was named SAP-1a. SAP-1b, a variant of SAP-1, has a truncated C-box region which lacks the six conserved carboxy-terminal (S/T)P motifs (Asp/Thr,Pro) (Treisman,
Curr. Opin. Genet. Dev
., 1994, 4, 96-101). SAP-1 mRNAs are ubiquitously expressed.
The role of SAP-1 in c-fos transactivation makes its selective inhibition a potential target with which to derive treatments for the tumorigenesis arising from its deregulation, as both viral and cellular Fos proteins have been implicated in the regulation of genes involved in tumor invasiveness. The functional nature of Fos as a transcription factor suggests that its constitutive presence in cells leads to the deregulation of its target genes (Gille et al.,
Mol. Cell. Biol
., 1996, 16, 1094-1102).
Generally disclosed in PCT publication WO 01/36674 are methods using antisense to inhibit the expression of marker genes, including SAP-1, which are implicated in prostate disorders. Also, claimed in the same publication are oligonucleotide probes capable of selectively hybridizing to said markers for the purpose of determining their expression levels (Bull et al., 2001).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SAP-1.
To date, there have been no investigative strategies aimed at modulating SAP-1 function. Consequently, there remains a long-felt need for agents capable of effectively inhibiting SAP-1 expression.
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 involving modulation of SAP-1 expression.
The present invention provides compositions and methods for modulating SAP-1 expression, including modulation of the truncated form of SAP-1, SAP-1b.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding SAP-1, and which modulate the expression of SAP-1. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of SAP-1 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 SAP-1 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 SAP-1, ultimately modulating the amount of SAP-1 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding SAP-1. As used herein, the terms “target nucleic acid” and “nucleic acid encoding SAP-1” encompass DNA encoding SAP-1, 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 SAP-1. 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 transcrib
ISIS Pharmaceuticals Inc.
Lacourciere Karen A
Licata & Tyrrell P.C.
Wang Andrew
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