Chimeric rna oligonucleotides and uses thereof

Abstract

The present invention relates to chimeric RNA oligonucleotides that are single-stranded oligonucleotides. These compounds are capable of targeting particular genes and reducing DNA methyltransferase activity. Accordingly, these compounds are particularly useful in the treatment of disease associated with aberrant DNA methyltransferase activity, such as cancer or a genetic disorder.

What is claimed is: 
     
         1 - 53 . (canceled) 
     
     
         54 . A method of reducing DNA methylation of a gene by a DNA methyltransferase (DNMT) in a subject in need thereof, comprising administering to the subject a target site specific, single-stranded synthesized RNA oligonucleotide comprising a sequence that is complementary to a promoter region of the gene, wherein said synthesized RNA oligonucleotide binds to the DNA methyltransferase (DNMT), thereby reducing the DNA methylation of the gene. 
     
     
         55 . The method of  claim 54 , wherein the subject has a disease or condition resulting from hypermethylation of the gene. 
     
     
         56 . The method of  claim 55 , wherein the disease or condition is cancer. 
     
     
         57 . The method of  claim 56 , wherein said cancer is selected from the group consisting of a myelodysplastic syndrome, leukemia, head and neck cancer, liver cancer, lung cancer, prostate cancer, skin cancer, retinoblastoma, glioblastoma, breast cancer, thyroid cancer, ovarian cancer, pancreatic cancer, brain cancer, kidney cancer, colon cancer, endometrial cancer, gastric cancer, multiple myeloma, and lymphoma. 
     
     
         58 . The method of  claim 57 , wherein said myelodysplastic syndrome is selected from the group consisting of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, refractory cytopenia with multilineage dysplasia, myelodysplastic syndrome associated with an isolated del(5q) chromosome abnormality, and a myeloproliferative neoplasm. 
     
     
         59 . The method of  claim 57 , wherein said cancer is acute myeloid leukemia, non-small cell lung cancer, small cell lung cancer, T-cell lymphoma, or glioblastoma. 
     
     
         60 . The method of  claim 55 , wherein the disease or condition is a genetic disorder. 
     
     
         61 . The method of  claim 60 , wherein said genetic disorder is an imprinting disorder, a disorder associated with loss of imprinting, a repeat instability disease, Beckwith-Wiedemann Syndrome (BWS), Prader-Willi Syndrome (PWS), Angelman Syndrome (AS), Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism type 1A (PHP-IA), pseudohypoparathyroidism type 1B (PHP-IB), loss of imprinting in IGF2/H19 for Wilms' tumor, Fragile X syndrome, or myotonic dystrophy. 
     
     
         62 . The method of  claim 54 , wherein said synthesized RNA oligonucleotide comprises a sequence of about 18 to about 35 nucleotides. 
     
     
         63 . The method of  claim 54 , wherein said synthesized RNA oligonucleotide is covalently or non-covalently linked to a targeting moiety or a carrier. 
     
     
         64 . The method of  claim 63 , wherein the targeting moiety is a cell-penetrating peptide. 
     
     
         65 . The method of  claim 63 , wherein the carrier is a condensing agent, a fusogenic agent, a protein targeting a particular cell or tissue type, a lipid, a polysaccharide, or a cationic moiety. 
     
     
         66 . The method of  claim 65 , wherein the condensing agent is a liposome. 
     
     
         67 . The method of  claim 54 , wherein said DNMT is selected from the group consisting of DNMT1, DNMT2, DNMT3a, DNMT3b, and DNMT3L. 
     
     
         68 . The method of  claim 54 , wherein synthesized RNA oligonucleotide further comprises a therapeutic agent, wherein said therapeutic agent is:
 a) a thiopurine;   b) a demethylating agent selected from the group consisting of 5-azacytidine and 5-aza-2′-deoxycytidine;   c) a DNA and/or RNA polymerase inhibitor selected from the group consisting of cytarabine, fludarabine, gemcitabine, cladribine, and clofarabine;   d) a thymidylate synthase inhibitor selected from the group consisting of 5-fluorouracil, floxuridine, capecitabine, tegafur, and carmofur;   e) an immunosuppressant that is azathioprine; or   f) an adenosine deaminase inhibitor that is pentostatin.   
     
     
         69 . The method of  claim 68 , wherein said thiopurine is thioguanine or mercaptopurine. 
     
     
         70 . The method of  claim 54 , wherein synthesized RNA oligonucleotide further comprises a label selected from the group consisting of an isotope, a radioimaging agent or a radiolabel, a fluorescent label, a nuclear magnetic resonance active label, a luminescent label, a chromophore label, a chemiluminescence label, an enzymatic label, a reporter molecule, an antibody, and an antibody fragment. 
     
     
         71 . The method of  claim 54 , wherein synthesized RNA oligonucleotide further comprises one or more modified nucleotides selected from the group consisting of 5-azacytidine, 5-aza-2′-deoxycytidine, fludarabine, clofarabine, azathioprine, floxuridine, mercaptopurine, thioguanine, pentostatin, and cladribine. 
     
     
         72 . The method of  claim 54 , wherein the method further comprises administration of a histone deacetylase (HDAC) inhibitor. 
     
     
         73 . The method of  claim 54 , wherein the subject is a human.