Oligonucleotide compositions and their use to induce differentiation of cells

Abstract

The present invention provides compositions comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, wherein the compositions are useful to induce differentiation of cells or to stimulate differentiation or production of pluripotent cells. The present invention provides methods of using these compositions to induce differentiation of pluripotent cells, including bone marrow derived cells, and to treat disease associated with insufficient differentiation of cells in animals and humans, including but not limited to leukemia, lymphoma, non-malignant blood disorders such as hemoglobinopathies, sickle cell disease, myelodysplastic syndrome, pancytopenia, anemia, thrombocytopenia and leukopenia.

1 . A composition comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, wherein the composition is effective to induce differentiation of cells, to increase cells derived from pluripotent cells, or to treat disease associated with insufficient differentiation of cells when administered to the cells in vivo or in vitro.  
     
     
         2 . The composition of  claim 1 , wherein the induction of differentiation of cells is induction of differentiation of leukemia cells.  
     
     
         3 . The composition of  claim 1 , wherein the induction of differentiation of cells is induction of differentiation of pluripotent stem cells, myeloid stem cells, lymphoid stem cells, progenitor cells, immune cell precursors, or cells derived from the pluripotent stem cells, the myeloid stem cells, the lymphoid stem cells, the progenitor cells, or the immune cell precursors.  
     
     
         4 . The composition of  claim 1 , wherein the disease is leukemia, lymphoma, a non-malignant blood disorder, hemoglobinopathy, sickle cell disease, myelodysplastic syndrome, pancytopenia, anemia, thrombocytopenia or leukopenia.  
     
     
         5 . A method comprising administration of an amount of a composition comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, to an animal or a human wherein the amount is effective to induce differentiation of cells in the animal or the human.  
     
     
         6 . The method of  claim 5 , wherein the animal or the human has a disease associated with insufficient differentiation of cells.  
     
     
         7 . The method of  claim 6 , wherein the disease is leukemia, lymphoma, a non-malignant blood disorder, hemoglobinopathy, sickle cell disease, myelodysplastic syndrome, pancytopenia, anemia, thrombocytopenia or leukopenia.  
     
     
         8 . The method of  claim 6 , wherein the disease is leukemia.  
     
     
         9 . The method of  claim 5 , wherein induction of differentiation of cells is induction of erythrocyte-like phenotype, monocyte-like phenotype, megakaryocyte-like phenotype, inhibition of proliferation or induction of hemoglobin synthesis in cells.  
     
     
         10 . A method comprising administration of an amount of a composition comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, to an animal or a human, wherein the amount is effective to increase differentiation of pluripotent cells in the animal or the human.  
     
     
         11 . The method of  claim 10 , wherein the animal or the human has received chemotherapy or radiotherapy.  
     
     
         12 . The method of  claim 4 , further comprising administration of a therapeutic agent.  
     
     
         13 . The method of  claim 12 , wherein the therapeutic agent is a chemotherapeutic drug, an immunosuppressive agent, a differentiating agent, an immunotherapeutic agent, an antimicrobial agent, an antiviral agent, radiotherapy, or a combination thereof.  
     
     
         14 . The method of  claim 10 , wherein the pluripotent cells are derived from bone marrow, liver, spleen, lymph nodes, thymus or cord blood.  
     
     
         15 . The method of  claim 10 , wherein the pluripotent cells are derived from bone marrow.  
     
     
         16 . A method comprising administration of an amount of a composition comprising a 3′-OH, 5′-OH, chemically unmodified, synthetic phosphodiester nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, and a pharmaceutically acceptable carrier, to an animal or a human having a disease associated with insufficient differentiation of cells, wherein the amount is effective to induce differentiation of cells in the animal or the human.  
     
     
         17 . The method of  claim 16 , wherein the disease is leukemia and the amount is effective to treat the leukemia.