Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
2000-01-21
2001-11-13
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, C536S023100, C536S024310, C536S024500
Reexamination Certificate
active
06316259
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides compositions and methods for modulating the expression of glycogen synthase kinase 3 alpha. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding glycogen synthase kinase 3 alpha. Such oligonucleotides have been shown to modulate the expression of glycogen synthase kinase 3 alpha.
BACKGROUND OF THE INVENTION
One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation, orchestrated by enzymes known as kinases, represents one course by which intracellular signals are propagated from molecule to molecule resulting in a cellular response. These signal transduction cascades are highly regulated and often overlapping as evidenced by the existence of many protein kinases as well as phosphatases, which remove phosphate moieties. 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 kinase cascades. Consequently, considerable attention has been devoted to the characterization of kinases, especially those involved in energy metabolism. One such kinase is glycogen synthase kinase 3.
Two different mammalian isoforms of glycogen synthase kinase 3 have been identified and each is encoded by a separate gene (Shaw et al.,
Genome,
1998, 41, 720-727; Woodgett,
Embo J.,
1990, 9, 2431-2438). These isoforms, designated alpha and beta are expressed in different cell types and in different proportions. In some cells, the expression of these isoforms is under developmental control.
Glycogen synthase kinase 3 alpha (also known as Factor A (Woodgett,
Embo J.,
1990, 9, 2431-2438) and ACLK for ATP citrate lyase kinase (Hughes et al.,
Biochem. J.,
1992, 288, 309-314)) is a serine/threonine protein kinase first described as a factor involved in glycogen synthesis. In this pathway, glycogen synthase kinase 3 phosphorylates select residues of glycogen synthase, the rate-limiting enzyme of glycogen deposition, thereby inactivating the enzyme. Therefore, glycogen synthase kinase 3 plays a predominant role in glycogen metabolism and has consequently been investigated as a potential therapeutic target in disease conditions such as diabetes and insulin regulation disorders (Cross et al.,
FEBS Lett.,
1997, 406, 211-215; Eldar-Finkelman et al.,
Proc. Natl. Acad. Sci. U. S. A.,
1996, 93, 10228-10233; Eldar-Finkelman and Krebs,
Proc. Natl. Acad. Sci. U. S. A.,
1997, 94, 9660-9664; Eldar-Finkelman et al.,
Diabetes,
1999, 48, 1662-1666).
Recently, it has been demonstrated that glycogen synthase kinase 3 alpha mediates signal transduction pathways by phosphorylating various cellular proteins (Plyte et al.,
Biochim. Biophys. Acta.,
1992, 1114, 147-162). Included in this group are transcription factors such as Jun family members (Nikolakaki et al.,
Oncogene,
1993, 8, 833-840), NF-ATc (Beals et al.,
Science,
1997, 275, 1930-1934), and CREB (Bullock and Habener,
Biochemistry,
1998, 37, 3795-3809) as well as proteins involved in apoptotic pathways (Pap and Cooper,
J. Biol. Chem.,
1998, 273, 19929-19932) and sperm motility (Smith et al.,
J. Androl.,
1999, 20, 47-53; Vijayaraghavan et al.,
Biol. Reprod.,
1996, 54, 709-718).
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of glycogen synthase kinase 3 alpha and to date, investigative strategies aimed at modulating glycogen synthase kinase 3 alpha function have involved the use of antibodies and chemical inhibitors. Disclosed in the PCT publication WO 97/41854 are methods to identify inhibitors of glycogen synthase kinase 3 and the use of these inhibitors for the treatment of bipolar disorders, mania, Alzheimer's disease, diabetes and leukopenia (Klein and Melton, 1997). Other inhibitory compounds are disclosed in WO 99/21859. These heterocyclic compounds are intended for the treatment of a disease mediated by a protein kinase, one of which is glycogen synthase kinase 3 (Cheung et al., 1999). There remains, however, a long felt need for additional agents capable of effectively inhibiting glycogen synthase kinase 3 alpha function. The pharmacological modulation of glycogen synthase kinase 3 alpha activity or expression may therefore be an appropriate point of therapeutic intervention in pathological conditions.
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 glycogen synthase kinase 3 alpha expression.
The present invention provides compositions and methods for modulating glycogen synthase kinase 3 alpha expression.
SUMMARY OF THE INVENTION
The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding glycogen synthase kinase 3 alpha, and which modulate the expression of glycogen synthase kinase 3 alpha. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of glycogen synthase kinase 3 alpha 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 glycogen synthase kinase 3 alpha 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 glycogen synthase kinase 3 alpha, ultimately modulating the amount of glycogen synthase kinase 3 alpha produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding glycogen synthase kinase 3 alpha. As used herein, the terms “target nucleic acid” and “nucleic acid encoding glycogen synthase kinase 3 alpha” encompass DNA encoding glycogen synthase kinase 3 alpha, 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 glycogen synthase kinase 3 alpha. 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
Butler Madeline M.
McKay Robert
Monia Brett P.
Wyatt Jacqueline
ISIS Pharmaceuticals Inc.
Larson Thomas G.
LeGuyader John L.
Licata & Tyrrell P.C.
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