Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-05-08
2004-10-26
Lacourciere, Karen A. (Department: 1635)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S024310, C536S024330, C435S006120, C435S091100, C435S325000, C435S366000, C435S375000
Reexamination Certificate
active
06809194
ABSTRACT:
TECHNICAL FIELD
The present invention provides methods and compositions for modulating the expression of Akt3, and antisense and ribozyme compounds specifically hybridizable with Akt3.
BACKGROUND OF THE INVENTION
Akt3 is one of three serine/threonine protein kinases implicated in mediating apoptosis, stimulating cell growth, and regulating other biological responses. Akt1 and Akt2 are also within this group. (Coffer, P. J. et al.,
Biochem. J
. 335:1-13, 1998.) Studies have suggested a role of Akt1 and Akt2 in cancer. For example, gene amplification resulted in increased Akt2 protein and mRNA in several cancers. (Staal, S. P. et al.,
P.N.A.S
. 84:5034-5037, 1987; Cheng, J. Q. et al.,
P.N.A.S
. 93:3636-3641, 1996; Cheng, J. et al.,
P.N.A.S
. 89:9267-9271.)
Due to its potential role in cancer, there is a need in the art for compositions and methods that regulate expression and/or function of each Akt protein, including Akt3.
SUMMARY OF THE INVENTION
The present invention provides, in one embodiment, inhibitors of Akt3. Inventive inhibitors include, but are not limited to, antisense molecules, ribozymes, antibodies or antibody fragments, proteins or polypeptides as well as small molecules. Exemplary antisense molecules comprise at least 10, 15 or 20 consecutive nucleotides of or hybridize under stringent conditions to the nucleic acid of SEQ ID NO:1. More preferred are antisense molecules that comprise at least 25 consecutive nucleotides of or hybridize under stringent conditions to the sequence of SEQ ID NO:1. Representative antisense molecules are provided herein as SEQ ID NOS:2-6 and 12-19.
In further embodiments, compositions are provided that comprise one or more Akt3 inhibitor in a pharmaceutically acceptable carrier.
Additional embodiments provide methods of decreasing Akt3 gene expression or biological activity.
The invention provides an antisense oligonucleotide comprising at least one modified internucleoside linkage.
The invention further provides an antisense oligonucleotide having a phosphorothioate linkage.
The invention still further provides an antisense oligonucleotide comprising at least one modified sugar moiety.
The invention also provides an antisense oligonucleotide comprising at least one modified sugar moiety which is a 2′-O-methoxyethyl sugar moiety.
The invention further provides an antisense oligonucleotide comprising at least one modified nucleobase.
The invention still further provides an antisense oligonucleotide having a modified nucleobase wherein the modified nucleobase is 5-methylcytosine.
The invention also provides an antisense compound wherein the antisense compound is a chimeric oligonucleotide.
The invention provides a method of inhibiting the expression of human Akt3 in human cells or tissues comprising contacting the cells or tissues in vivo with an antisense compound or a ribozyme of 8 to 35 nucleotides in length targeted to a nucleic acid molecule encoding human Akt3 so that expression of human Akt3 is inhibited.
The invention further provides a method of modulating growth of cancer cells comprising contacting the cancer cells in vivo with an antisense compound or ribozyme of 8 to 35 nucleotides in length targeted to a nucleic acid molecule encoding human Akt3 so that expression of human Akt3 is inhibited.
The invention still further provides for identifying target regions of Akt3 polynucleotides. The invention also provides labeled probes for identifying Akt3 polynucleotides by in situ hybridization.
The invention provides for the use of an Akt3 inhibitor according to the invention to prepare a medicament for modulating cell proliferation.
The invention also provides a pharmaceutical composition for inhibiting expression of the Akt3, comprising an antisense oligonucleotide according to the invention in admixture with a physiologically acceptable carrier or diluent.
The invention further provides a ribozyme capable of specifically cleaving Akt3 RNA, and a pharmaceutical composition comprising the ribozyme.
The invention also provides small molecule inhibitors of Akt3 wherein the inhibitors are capable of reducing the activity of Akt3 or of reducing or preventing the expression of Akt3 mRNA.
REFERENCES:
patent: 5958773 (1999-09-01), Monia et al.
patent: 6187586 (2001-02-01), Monia et al.
Jen et al., Stem Cells, vol. 18, pp. 307-319, 2000.*
Green et al. J. of Am. Coll. Surg. vol. 191, No. 1, Jul. 2000.*
Agrawal et al. Molecular Medicine Today, vol. 6, pp; 72-81, Feb. 2000.*
Ma et al., Biotechnology Annula Review, vol. 5, pp. 155-196, 2000.*
Branch, TIBS 23, pp. 45-50, Feb. 1998.*
Flanagan et al., Nature Biotechnology, vol. 17, No. 1, pp. 48-52, Jan. 1999.*
Bennett et al. “Pharmacology of Antisense Therapeutic Agents”, Chapter 2, from Methods in Molecular Medicine: Antisense Therapeutics, Ed. S. Agrawal, Humana Press Inc., Totowa, NJ, ISBN: 0_89603-305-8, 1996.*
Masure et al., Eur. J. Biochem., vol. 265, pp. 353-360, 1999.*
Konishi et al. Biochemical and Biophysical Research Communications, vol. 216, No. 2, Nov. 13, 1995, pp. 526-534.*
Nakatani et al., Biochemical and Biophysical Research Communications, vol. 257, pp. 906-910, 1999.*
Brodbeck et al., The Journal of Biological Chemistry, vol. 274, No. 14, pp. 9133-9136, 1999.*
Alessi et al., “Mechanism of activation and function of protein kinase B,”Current Opinion in Genetics&Development 8(1):55-62, Feb. 1998.
Bellacosa et al., “Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas,”International J. Cancer 64(4):280-285, Aug. 22, 1995.
Boe, “A target for phosphoinositide 3-kinase: Akt/PKB,”Trends Biochem. Sci. 20:441-442, Nov. 1995.
Cheng et al., “AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplifed in human ovarian carcinomas,”P.N.A.S. U.S.A. 89:9267-9271, Oct. 1992.
Cheng et al., “Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA,”P.N.A.S. U.S.A. 93:3636-3641, Apr. 1996.
Coffer et al., “Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation,”Biochem. J. 335:1-13, 1998.
Downward, “Mechanisms and consequences of activation of protein kinase B/Akt,”Current Opinion in Cell Biology 10(2):262-267, Apr. 1998.
Nakatani et al., “Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines,”J. Biol. Chem. 274(31):21528-21532, Jul. 1999.
Staal, “Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma,”P.N.A.S. U.S.A. 84(14):5034-5037, Jul. 1987.
Jefferson Anne B.
Reinhard Christoph
Blackburn Robert P.
Chiron Corporation
Lacourciere Karen A.
Launer Charlene A.
Potter Jane E. R.
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