Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-09-14
2003-09-30
Prouty, Rebecca E. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S193000, C435S194000, C435S006120, C536S023200, C536S024500, C536S023500
Reexamination Certificate
active
06627619
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides TRT antisense oligonucleotides, methods of detecting TRT, methods of diagnosing telomerase-related conditions, methods of diagnosing and providing a prognosis for cancer, and methods of treating telomerase-related conditions, including cancer, with TRT antisense oligonucleotides.
BACKGROUND OF THE INVENTION
The following discussion is intended to introduce the field of the present invention to the reader. The citation of various references in this section should not be construed as an admission of prior invention.
It has long been recognized that complete replication of the ends of eukaryotic chromosomes requires specialized cell components (Watson, 1972,
Nature New Biol.,
239:197; Olovnikov, 1973,
J. Theor. Biol.,
41:181). Replication of a linear DNA strand by conventional DNA polymerases requires an RNA primer, and can proceed only 5′ to 3′. When the RNA bound at the extreme 5′ ends of eukaryotic chromosomal DNA strands is removed, a gap is introduced, leading to a progressive shortening of daughter strands with each round of replication. This shortening of telomeres, the protein-DNA structures physically located on the ends of chromosomes, is thought to account for the phenomenon of cellular senescence or aging of normal human somatic cells in vitro and in vivo. The length and integrity of telomeres is thus related to entry of a cell into a senescent stage (i.e., loss of proliferative capacity), or the ability of a cell to escape senescence, i.e., to become immortal. The maintenance of telomeres is a function of a telomere-specific DNA polymerase known as telomerase. Telomerase is a ribonucleoprotein (RNP) that uses a portion of its RNA moiety as a template for telomeric DNA synthesis (Morin, 1997,
Eur. J. Cancer
33:750).
Consistent with the relationship of telomeres and telomerase to the proliferative capacity of a cell (i.e., the ability of the cell to divide indefinitely), telomerase activity is detected in immortal cell lines and an extraordinarily diverse set of tumor tissues, but is not detected (i.e., was absent or below the assay threshold) in normal somatic cell cultures or normal tissues adjacent to a tumor (see, U.S. Pat. Nos. 5,629,154; 5,489,508; 5,648,215; and 5,639,613; see also, Morin, 1989,
Cell
59: 521; Shay and Bacchetti 1997,
Eur. J. Cancer
33:787; Kim et al., 1994,
Science
266:2011; Counter et al., 1992,
EMBO J.
11:1921; Counter et al., 1994,
Proc. Natl. Acad. Sci. U.S.A.
91, 2900; Counter et al., 1994,
J. Virol.
68:3410). Moreover, a correlation between the level of telomerase activity in a tumor and the likely clinical outcome of the patient has been reported (e.g., U.S. Pat. No. 5,639,613, supra; Langford et al., 1997,
Hum. Pathol.
28:416). Human telomerase is thus an ideal target for diagnosing and treating human diseases relating to cellular proliferation and senescence, such as cancer.
SUMMARY OF THE INVENTION
The present invention provides TRT antisense polynucleotides, which are useful for detecting, diagnosing, and treating telomerase-related conditions.
In one aspect, the present invention provides an isolated, synthetic, substantially pure, or recombinant polynucleotide having a sequence that is at least about ten nucleotides in length to at least about 100 nucleotides in length. This polynucleotide comprises a sequence that is substantially complementary or substantially identical to a contiguous sequence of an hTRT nucleic acid that has the nucleotide sequence of FIG.
1
.
In one aspect, the present invention provides an isolated, synthetic, substantially pure, or recombinant polynucleotide having a sequence that is at least about ten nucleotides in length to at least about 100 nucleotides in length. This polynucleotide comprises a sequence exactly complementary or identical to a contiguous sequence of a nucleic acid encoding the hTRT protein of FIG.
2
.
In one embodiment, the hTRT polynucleotide comprises a sequence that is exactly complementary or identical to a contiguous sequence of an hTRT nucleic acid having the nucleotide sequence of FIG.
1
.
In one embodiment, the polynucleotide is a DNA or an RNA. In one embodiment, the polynucleotide comprises one or more non-naturally occurring, synthetic nucleotides.
In one embodiment, the polynucleotide is identical to said contiguous sequence of a nucleic acid encoding the hTRT protein of FIG.
1
. In one embodiment, the polynucleotide is exactly complementary to said contiguous sequence of a nucleic acid encoding the hTRT protein of FIG.
1
.
In one embodiment, the polynucleotide is an antisense polynucleotide. In one embodiment, the polynucleotide is at least about 20 nucleotides in length to at least about 50 nucleotides in length.
In one embodiment, the polynucleotide inhibits telomerase activity by at least about 50% in transformed cells ex vivo, as compared to control cells that are not treated with the polynucleotide. In one embodiment, the polynucleotide inhibits telomerase expression by at least about 50% in vitro, as compared to control expression reactions that lack the polynucleotide. In one embodiment, the polynucleotide is selected from the group consisting of phosphorothioate oligonucleotide (PS-ODN) number 3, 4, 7, 8, 16, 21, 25, 26, 27, 28, 29, 33, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 62, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 80, 81, 82, 83, 84, 85, 86, 87, 88, 93, 94, 96, 100, 112, 114, 130, 143, 144, 151, 152, 201, 202, 203, 208, 209, 210, 211, 212, 213, 230, 237, and 241.
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patent: WO 97/38013 (1997-10-01), None
Adams M. et al. Initial Assessment of Human Gene Diversity and Expression Patterns Based upon 83 Million Nucleotides of cDNA Sequence. Nature, 377, supp. Sep. 28, 1995, 3-174.*
Lanfranchi G. et al. Identification of 4370 Expressed Sequence Tags from a 3'-End-Specific cDNA library of Human Skeletal Muscle by DNA Sequencing and Filter Hybridization, Genome Res., 6, 1996, 35-42.*
Bonaldo M. et al. Normalization and Subtraction: Two Approaches to Facilitate Gene Discovery, Genome Res. 6, 1996, 791-806.*
Harrington, Lea et al. (1997) “A Mammalian Telomerase-Associated Protein”,Science275:973-977.
Langford, Lauren A., et al. (1997) “Telomerase Activity in Ordinary Meningiomas Predicts Poor Outcome”,Human Pathology28(4):416-420.
Nakamura, Toru, M., et al. (1997) “Telomerase Catalytic Subunit Homologs from Fission Yeast and Human”,Science.277:955-959.
Harrington, Lea, et al. (1995) “Gel Shift and UV Cross-linking Analysis ofTetrahymenaTelomerase”,The Journal of Biological Chemistry, 270(15):8893-8901.
Collins, Kathleen, et al. (1995) “Purification of Tetrahymena Telomerase and Cloning of Genes Encoding the Two Protein Components of the Enzyme”,Cell, 81:677-686.
Greider, Carol W. (1998) Telomerase and senescence: The history, experiment, the future,Current Biology, 8(5):R178-R181.
Kilian, Andrzej, et al. (1997) “Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types”,Human Molecular Genetics, 6(12):2011-2019.
Meyerson, Matthew, et al. (1997) “hEST2, the Putative Human Telomerase Catalytic Subunit Gene, Is Up-Regulated in Tumor Cells and during Immortalization”,Cell90:785-795.
Morin, G.B. (1997) “The Implications of Telomerase Biochemistry for Human Disease”,European Journal of Cancer, 33(5):750-760.
EST, Accession No. AA281296, NCBI database, 1997.
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EST, Accession No. AA299878, NCBI database, 1997.
Andrews William H.
Cech Thomas R.
Chapman Karen B.
Harley Calvin B.
Lingner Joachim
Earp David J.
Geron Corporation
Prouty Rebecca E.
Schiff J. Michael
Townsend & Townsend & Crew LLP
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