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Oligonucleotide compositions and their use to induce differentiation of cellsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.)Oligonucleotide compositions and their use to induce differentiation of cells description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070010472, Oligonucleotide compositions and their use to induce differentiation of cells. Brief Patent Description - Full Patent Description - Patent Application Claims
PRIOR RELATED APPLICATIONS [0001] The present application claims priority to U.S. provisional patent application Ser. No. 60/286,158 filed Apr. 24, 2001. This application is a divisional of U.S. patent application Ser. No. 10/127,645 filed Apr. 22, 2002, now allowed, the contents of which are incorporated herein by reference. SEQUENCE LISTING [0002] The content of the sequence listing information is identical to the paper sequence listing provided in U.S. patent application Ser. No. 10/127,645 filed Apr. 22, 2002, and includes no new matter. FIELD OF THE INVENTION [0003] The present invention provides compositions comprising specific oligonucleotides combined with a pharmaceutically acceptable carrier, wherein the compositions are useful to induce differentiation of cells, including pluripotent cells, leukemic cells, lymphoma cells and bone marrow-derived cells, and to treat diseases such as leukemia, lymphoma and disorders associated with insufficient differentiation of cells. BACKGROUND OF THE INVENTION [0004] Numerous diseases and conditions in animals and humans are associated with insufficient differentiation of cells or with an insufficiency of cells. Many of these cells are derived from bone marrow. Such diseases and conditions include but are not limited to leukemia, lymphoma, and non-malignant blood disorders such as hemoglobinopathies, sickle cell disease, myelodysplastic syndrome and insufficient production of bone marrow derived cells following therapies such as radiation and chemotherapy. [0005] Differentiation therapy of leukemia cells in diseases such as acute promyelocytic leukemia (APL), acute myeloid leukemia (AML), chronic promyelocytic leukemia (CPL) and chronic myeloid leukemia (CML), has provided an alternative strategy for the treatment of leukemia. In differentiation therapy, immature leukemia cells are induced by different chemical compounds to attain a mature phenotype resulting in arrest of their growth. [0006] A number of differentiation compounds and also radiation have been reported to induce the differentiation of leukemia cells. Hemin, butyric acid, 5-azacytidine, cytosine arabinoside, hydroxyurea, guanosine, guanine, retinoic acid, trimidox, gamma-irradiation, mithramycin and chromomycin have been reported to induce differentiation of leukemia cells (Rutherford et al., Nature 280:164, 1979; Gambari et al., Biochem. Biophys. Acta, 886:203, 1986; Bianchi et al., Cancer Res. 46:6327, 1986; Adunyah et al., Biochem. Biophys. Acta, 1263:123, 1995; Osti et al., Haematologica 82:395, 1997; Cortesi et al., Eur. J. Haematol. 61:295, 1998; Iyamu et al., Biochem. Biophys. Res. Com. 247:759, 1998; Schwenke et al., Leuk. Res. 19:955, 1995; and Bianchi et al., Br. J. Haematol. 104:258, 1999). [0007] Synthetic oligonucleotides are polyanionic sequences that are internalized in cells (Vlassov et al. Biochim. Biophys. Acta 1197:95, 1994). Synthetic oligonucleotides are reported to bind selectively to nucleic acids (Wagner, R. Nature: 372:333, 1994), to specific cellular proteins (Bates et al. J. Biol. Chem. 274:26369, 1999) and to specific nuclear proteins (Scaggiante et al. Eur. J. Biochem. 252:207, 1998), and to inhibit proliferation of cancer cells. Synthetic oligonucleotides have not been reported to possess differentiating activity on acute and/or chronic pro-myelocytic cells and/or myeloid leukemia cells. Synthetic phosphorothioate oligonucleotides having a CpG motif (5'purine-purine-cytosine (C)-guanine (G)-pyrimidine-pyrimidine3') have been shown to induce the proliferation of B-cell chronic lymphocytic leukemia (Decker et al., Blood 95:999, 2000). Synthetic 27 base sequences containing G and variable amounts of thymine (T), hereinafter oligonucleotide GTn, wherein n is .gtoreq.1 or .ltoreq.7 Ts (Scaggiante et al., Eur. J. Biochem. 252:207, 1998), and wherein the number of bases is >20 (Morassutti et al., Nucleosides and Nucleotides 18:1711, 1999), have been reported to inhibit growth of leukemia cells by sequence specific binding to a 45 kDa nuclear protein. In contrast, GTn sequences, wherein the total number of bases is less than 15, are reported to be inactive against these cells (Morassutti et al. Nucleosides and Nucleotides 18:1711, 1999). Chimeric methylphosphonodiester/phosphodiester oligonucleotides of sequence type SEQ ID NO:5 CGNNN (N=A, C, G or T), introduced into the cytoplasm of cells by 10 minutes of reversible permeabilization with streptolysin O, induce apoptosis of human T cell leukemia cells. Nevertheless, the CGNNN oligonucleotides are reported to be inactive against three CML cell lines (K562, LAMA84 and KYO1), showing no significant effect on the growth and survival of these cells (Tidd et al., Nucleic Acid Res. 28:2242, 2000). [0008] Depletion of bone marrow derived cells is observed in several conditions, including depletion following radiation therapy or chemotherapy. Insufficient production of cells destined to become erythrocytes or granulocytes is associated with numerous problems, including but not limited to, reduced delivery of oxygen to cells, decreased immune function, and clotting abnormalities. Various therapies, including expensive chemotherapies, are often required to stimulate production of red and white cells. [0009] Most prior art differentiating therapies have proven to be less than adequate for clinical applications. Many of these therapies are inefficient or toxic, have significant adverse effects and are debilitating for the recipient. Therefore, there is a continuing need for novel compositions and methods that induce differentiation of cells such as myeloid-derived leukemia cells. What is also needed are new therapeutic compositions and methods that stimulate production and differentiation of pluripotent cells such as bone-marrow derived cells. Also needed are new therapeutic compositions that induce differentiation of cells. What is also needed are compositions and methods that may be used to treat diseases and conditions characterized by insufficient differentiation of cells or insufficient production of marrow derived cells. SUMMARY OF THE INVENTION [0010] The present invention fulfills these needs by providing a method comprising administration of a composition comprising a 3'-OH, 5'-OH, chemically unmodified, synthetic phosphodiester oligonucleotide sequence (hereinafter sequence) selected from the group consisting of SEQ ID NO: 1 (5'GTG3'), SEQ ID NO: 2 (5'GGGTGG3'), SEQ ID NO: 3 (5'GGGAGG3') and SEQ ID NO: 4 (5'CCACCC3') and a pharmaceutically acceptable carrier, wherein the composition induces differentiation of cells. The present invention provides a method to treat diseases associated with growth of cells that are not differentiated to a mature phenotype. Terminal differentiation of cells may include one or more responses selected from the group consisting of induction of erythrocyte-like phenotype, monocyte-like phenotype, megakaryocyte-like phenotype, inhibition of proliferation of leukemia cells and induction of hemoglobin synthesis. [0011] The compositions of the present invention may be used to treat diseases related to insufficient differentiation of cells. Such diseases include but are not limited to leukemia, lymphoma, and non-malignant blood disorders such as hemoglobinopathies, sickle cell disease or myelodysplastic syndrome. The compositions of the present invention are believed to be useful for treatment of pancytopenia, anemia, thrombocytopenia and leukopenia. Other conditions that may be treated with the compositions of the present invention include lymphoma and nonmalignant blood disorders, including but not limited to hemoglobinopathies, sickle cell disease and myelodysplastic syndromes. In a preferred embodiment, the compositions of the present invention are administered to an animal or a human with leukemia in an amount effective to treat the leukemia. [0012] The compositions of the present invention may also be administered to an animal or human together with other therapies as a combination therapy. These therapies may include administration of therapeutic compounds or radiation therapy. The compositions of the present invention may be administered before, after, or concomitantly with the other therapy. Such combination therapy may augment the net therapeutic effect on the animal or human. The compositions of the present invention may be administered alone, or in combination with other therapeutic modalities including, but not limited to, chemotherapeutic agents, differentiating agents, immunotherapeutic agents, antimicrobial agents, antiviral agents or in combination with radiation therapy. [0013] The compositions of the present invention may be administered to a recipient to stimulate production of cells after other therapies administered to the recipient have depleted such cells. One non-limiting example involves depletion of cells derived from bone marrow following radiation therapy or chemotherapy. The compositions of the present invention may also be administered to a recipient to stimulate production and differentiation of other cells such as pluripotent stem cells, myeloid stem cells, lymphoid stem cells, progenitor cells, immune cell precursors, and/or other cells derived from these pluripotent stem cells, myeloid stem cells, lymphoid stem cells, progenitor cells, and immune cell precursors. The compositions of the present invention may also be administered to a recipient to stimulate production and differentiation of cells from numerous sources, including but not limited to, bone marrow, liver, spleen, lymph nodes, thymus and cord blood. [0014] The compositions of the present invention may also be administered in vitro to affect differentiation of cells such as pluripotent stem cells, myeloid stem cells, lymphoid stem cells, progenitor cells, immune cell precursors, and/or other cells derived from these pluripotent stem cells, myeloid stem cells, lymphoid stem cells, progenitor cells, and immune cell precursors. [0015] The unexpected and surprising ability of the composition of the present invention to induce differentiation of bone-marrow derived cells, including leukemia cells, addresses a long-felt, unfulfilled need in the medical arts and provides an important benefit for animals and humans. [0016] Accordingly, it is an object of the present invention to provide a method comprising administration of a composition comprising a 3'-OH, 5'-OH, chemically unmodified, synthetic phosphodiester oligonucleotide sequence (hereinafter sequence) selected from the group consisting of SEQ ID NO: 1 (5'GTG3'), SEQ ID NO: 2 (5'GGGTGG3'), SEQ ID NO: 3 (5'GGGAGG3') and SEQ ID NO: 4 (5'CCACCC3') and a pharmaceutically acceptable carrier to treat disease in animals and humans, wherein the disease is characterized by insufficient differentiation of cells. [0017] Another object of the present invention is to provide a method comprising administration of a composition comprising a 3'-OH, 5'-OH, chemically unmodified, synthetic phosphodiester oligonucleotide sequence (hereinafter sequence) selected from the group consisting of SEQ ID NO: 1 (5'GTG3'), SEQ ID NO: 2 (5'GGGTGG3'), SEQ ID NO: 3 (5'GGGAGG3') and SEQ ID NO: 4 (5'CCACCC3') and a pharmaceutically acceptable carrier to induce progenitor cell maturation and differentiation in animals and humans. [0018] Another object of the present invention is to provide a composition and method to treat leukemia. [0019] Yet another object of the present invention is to provide a method that inhibits proliferation of leukemic cells and induces differentiation of leukemic cells. Continue reading about Oligonucleotide compositions and their use to induce differentiation of cells... 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