Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2001-05-10
2002-09-03
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
06444466
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of helicase-moi. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding helicase-moi. Such compounds have been shown to modulate the expression of helicase-moi.
BACKGROUND OF THE INVENTION
In addition to functioning as genetic transcripts, RNA molecules play structural and even catalytic roles. Depending on their specific cellular roles, RNA molecules can be largely single stranded or adopt specific tertiary structures. A variety of proteins are necessary to assure the correct folding of RNA molecules and to maintain or modify their specific secondary or tertiary structures. Among these proteins are the RNA helicases of the DEAD-box family and related families (de la Cruz et al.,
Trends Biochem. Sci
., 1999, 24, 192-198). These are involved in various aspects of RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and gene expression. Although generally assumed to be a double-stranded RNA, the substrate might also be an RNA-protein complex. Some investigators therefore refer to these proteins as RNA-dependent NTPases or RNA unwindases, to distinguish them from the processive DNA helicases (de la Cruz et al.,
Trends Biochem. Sci
., 1999, 24, 192-198).
More recently, helicases have been implicated in the process of posttranscriptional gene silencing (PTGS), a form of RNA-mediated interference (Cogoni and Macino,
Science
, 1999, 286, 2342-2344). In this process, the helicase is required to separate the double-stranded DNA before any hybridization and silencing mechanism can be initiated.
The DEAD and DEAH helicase families are closely related helicase groups with their names derived from the sequence of the Walker B motif (DEAD=Asp-Glu-Ala-Asp; DEAH=Asp-Glu-Ala-His) (reviewed in (de la Cruz et al.,
Trends Biochem. Sci
., 1999, 24, 192-198)). The DEXH family is a variation on the DEAH family wherein the third amino acid in the DEAH sequence is variable.
Helicase-moi (also known as KIAA0928, HERNA, delta-K12H4.8 homologue and HEMBA1004199) is a recently discovered helicase gene that encodes a protein belonging to the DEXH-box helicase family (Matsuda et al.,
Biochim. Biophys. Acta
, 2000, 1490, 163-169; Nagase et al.,
DNA Res
., 1999, 6, 63-70; Provost et al.,
Proc. Natl. Acad. Sci. U. S. A
., 1999, 96, 1881-1885). In human tissues, helicase-moi is expressed in brain, lung, liver, pancreas and kidney and the gene has been localized to chromosome 14q31 (Matsuda et al.,
Biochim. Biophys. Acta
, 2000, 1490, 163-169). Other genes that have been mapped to 14q31 are potential targets involved in Krabble disease, ovarian cancer, and Graves' disease (Matsuda et al.,
Biochim. Biophys. Acta
, 2000, 1490, 163-169).
Helicase-moi has been found to interact strongly with the enzyme 5-lipoxygenase which plays a central role in cellular leukotriene synthesis (Provost et al.,
Proc. Natl. Acad. Sci. U. S. A
., 1999, 96, 1881-1885). Since leukotrienes are mediators of inflammation, selective inhibition of potential regulators of leukotriene synthesis, such as helicase-moi, may prove to be an efficient strategy with which to derive treatments for inflammatory disorders. To date, specific inhibitors for helicase-moi have yet to be developed or identified. Consequently, there remains a long felt need for agents capable of effectively and selectively inhibiting the function of helicase-moi.
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 expression of helicase-moi.
The present invention provides compositions and methods for modulating expression of helicase-moi.
SUMMARY OF THE INVENTION
The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding helicase-moi, and which modulate the expression of helicase-moi. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of helicase-moi 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 helicase-moi 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 helicase-moi, ultimately modulating the amount of helicase-moi produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding helicase-moi. As used herein, the terms “target nucleic acid” and “nucleic acid encoding helicase-moi” encompass DNA encoding helicase-moi, 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 helicase-moi. 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 helicase-moi. 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 “trans
Ward Donna T.
Watt Andrew T.
ISIS Pharmaceuticals Inc.
LeGuyader John L.
Licata & Tyrrell P.C.
Schmidt Mary M.
LandOfFree
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