Antisense IAP nucleobase oligomers and uses thereof

Abstract

The present invention features nucleobase oligomers that hybridize to IAP polynucleotides, and methods for using them to enhance apoptosis.

1 . A method of treating an animal having a lymphoproliferative disorder, the method comprising: administering to the animal in need thereof an IAP nucleobase oligomer of up to 30 nucleobases in length, the nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NOs: 1-96, 97-162 and 278-292, thereby treating the animal.  
     
     
         2 . The method, according to  claim 1 , in which the nucleobase oligomer comprises at least eight consecutive nucleobases of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         3 . The method, according to  claim 2 , in which the nucleobase oligomer comprises at least eight consecutive nucleobases of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         4 . The method, according to  claim 3 , in which the nucleobase oligomer consists essentially of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         5 . The method, according to  claim 4 , in which the nucleobase oligomer consists of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         6 . The method, according to  claim 1 , in which the nucleobase oligomer is an oligonucleotide.  
     
     
         7 . The method, according to  claim 6 , in which the oligonucleotide comprises at least one modified linkage.  
     
     
         8 . The method, according to  claim 7 , in which the modified linkage is selected from the group consisting of phosphorothioate, methylphosphonate, phosphotriester, phosphorodithioate, and phosphoselenate linkages.  
     
     
         9 . The method, according to  claim 1 , in which the nucleobase oligomer comprises at least one modified sugar moiety.  
     
     
         10 . The method, according to  claim 9 , in which the modified sugar moiety is a 2′-O-methyl group or a 2′-O-methoxyethyl group.  
     
     
         11 . The method, according to  claim 1 , in which the nucleobase oligomer comprises at least one modified nucleobase.  
     
     
         12 . The method, according to  claim 11 , in which the modified nucleobase is 5-methyl cytosine.  
     
     
         13 . The method, according to  claim 1 , in which the nucleobase oligomer is a chimeric nucleobase oligomer.  
     
     
         14 . The method, according to  claim 13 , in which the nucleobase oligomer comprises DNA residues linked together by phosphorothioate linkages, the DNA residues flanked on each side by at least one 2′-O-methyl or 2′-O-methoxyethyl RNA residue.  
     
     
         15 . The method, according to  claim 14 , in which the DNA residues are flanked on each side by at least three 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         16 . The method, according to  claim 15 , in which the DNA residues are flanked on each side by four 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         17 . The method, according to  claim 14 , in which the RNA residues are linked together by phosphorothioate linkages, and the RNA residues are linked to the DNA residues by phosphorothioate linkages.  
     
     
         18 . The method, according to  claim 13 , in which the nucleobase oligomer comprises DNA residues linked together by phosphodiester linkages, the DNA residues flanked on each side by at least two 2′-O-methyl or 2′-O-methoxyethyl RNA residues linked together by phosphorothioate linkages.  
     
     
         19 . The method, according to  claim 18 , in which the DNA residues are flanked on each side by at least three 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         20 . The nucleobase oligomer of  claim 1 , the nucleobase oligomer comprising eleven DNA residues flanked on each side by four 2′-O-methyl RNA residues, the nucleobase oligomer consisting of SEQ ID NOs: 16, 27, 41, 47, 51,63,141, 151,155, 157 and 161, the residues linked together by phosphorothioate linkages.  
     
     
         21 . The method of  claim 1 , further comprising administering to the animal a biological response-modifying agent.  
     
     
         22 . The method, according to  claim 21 , in which the biological response-modifying agent is an interferon.  
     
     
         23 . The method, according to  claim 22 , in which the interferon is interferon alpha, interferon beta, or interferon gamma.  
     
     
         24 . The method, according to  claim 1 , in which the lymphoproliferative disorder is multiple sclerosis, Crohn's disease, lupus erythematosis, rheumatoid arthritis, or osteoarthritis.  
     
     
         25 . The method, according to  claim 24 , in which the lymphoproliferative disorder is multiple sclerosis.  
     
     
         26 . The method, according to  claim 1 , in which the nucleobase oligomer is administered to the animal intravenously.  
     
     
         27 . The method, according to  claim 1 , in which the animal is a human.  
     
     
         28 . A composition comprising: (i) an IAP nucleobase oligomer of up to 30 nucleobases in length, the nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NOs: 1-96, 97-162 and 278-292; and (ii) a biological response-modifying agent, in amounts that together are sufficient to treat an animal having a lymphoproliferative disorder.  
     
     
         29 . The composition, according to  claim 28 , in which the nucleobase oligomer comprises at least eight consecutive nucleobases of a sequence selected from the group consisting of: SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         30 . The composition, according to  claim 29 , in which the nucleobase oligomer comprises at least eight consecutive nucleobases of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         31 . The composition, according to  claim 30 , in which the nucleobase oligomer consists essentially of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         32 . The composition of  claim 31 , in which the nucleobase oligomer consists of a sequence selected from the group consisting of SEQ ID NOs: 1-96, 97-162 and 278-292.  
     
     
         33 . A method of enhancing apoptosis of a cell in an animal, the method comprising: administering to the animal the composition, according to  claim 28 , in amounts that inhibits expression of an IAP in the cell.  
     
     
         34 . The method, according to  claim 33 , in which the cell is in vivo.  
     
     
         35 . The method, according to  claim 33 , in which the cell is ex vivo.  
     
     
         36 . The method, according to  claim 33 , in which the cell is of lymphoid origin.  
     
     
         37 . The method, according to  claim 33 , in which the cell is a T cell.  
     
     
         38 . The method, according to  claim 33 , in which the cell is a B-cell.  
     
     
         39 . A method of treating a human having multiple sclerosis, the method comprising: administering to the patient in need thereof an IAP nucleobase oligomer of up to 30 nucleobases in length, the nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NOs: 1-96, 97-162 and 278-292, thereby treating the human.  
     
     
         40 . A method of treating a human having multiple sclerosis, the method comprising administering to the patient: (i) an IAP nucleobase oligomer of up to 30 nucleobases in length, the nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NOs: 1-96, 97-162 and 278-292; and (ii) an interferon in amounts that together are sufficient to treat the human.  
     
     
         41 . A method of treating an animal having a lymphoproliferative disorder, the method comprising administering to the animal an effective amount of a catalytic RNA molecule capable of cleaving XIAP mRNA, thereby treating the animal.  
     
     
         42 . The method, according to  claim 41 , in which the binding arms of the catalytic RNA molecule contain at least eight consecutive nucleobases corresponding to a sequence of any one of Tables 1 or 2.  
     
     
         43 . The method, according to  claim 42 , in which the RNA molecule is in a hammerhead motif.  
     
     
         44 . The method, according to  claim 41 , in which the RNA molecule is in a hairpin, hepatitis delta virus, group 1 intron, VS RNA or RNAseP RNA motif.  
     
     
         45 . A method of treating an animal having a lymphoproliferative disorder, the method comprising administering to the animal an effective amount of a double-stranded RNA molecule consisting of between 21 and 29 nucleobases, the RNA molecule comprising at least eight consecutive nucleobases corresponding to a sequence of any one of Tables 1 and 2.  
     
     
         46 . A method of treating an animal having a lymphoproliferative disorder, the method comprising administering to the animal an effective amount of a double-stranded hairpin RNA molecule consisting of between 50 and 70 nucleobases, the RNA molecule comprising a first domain of between 21 and nucleobases that comprise least eight consecutive nucleobases corresponding to a sequence of any one of Tables 1 and 2; a second domain complementary to the first domain, and a loop domain situated between the first and the second domains such that the first domain and the second domain are capable of duplexing to form the double-stranded hairpin RNA molecule.