Antisense IAP nucleobase oligomers and uses thereof

Abstract

The present invention features nucleobase oligomers that hybridize to IAP polynuclotides, and methods for using them to enhance apoptosis and treat proliferative diseases.

1 . A substantially pure nucleobase oligomer of up to 30 nucleobases in length, said nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NO: 97.  
     
     
         2 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer consists essentially of SEQ ID NO: 97.  
     
     
         3 . The nucleobase oligomer of  claim 2 , wherein said nucleobase oligomer consists of SEQ ID NOs: 97.  
     
     
         4 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer is an oligonucleotide.  
     
     
         5 . The nucleobase oligomer of  claim 1 , wherein said oligonucleotide comprises at least one modified linkage.  
     
     
         6 . The nucleobase oligomer of  claim 5 , wherein said modified linkage is selected from the group consisting of phosphorothioate, methylphosphonate, phosphotriester, phosphorodithioate, and phosphoselenate linkages.  
     
     
         7 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer comprises at least one modified sugar moiety.  
     
     
         8 . The nucleobase oligomer of  claim 7 , wherein said modified sugar moiety is a 2′-O-methyl group or a 2′-O-methoxyethyl group.  
     
     
         9 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer comprises at least one modified nucleobase.  
     
     
         10 . The nucleobase oligomer of  claim 9  wherein said modified nucleobase is 5-methyl cytosine.  
     
     
         11 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer is a chimeric nucleobase oligomer.  
     
     
         12 . The nucleobase oligomer of  claim 11 , wherein said nucleobase oligomer comprises DNA residues linked together by phosphorothioate linkages, said DNA residues flanked on each side by at least one 2′-O-methyl or 2′-O-methoxyethyl RNA residue.  
     
     
         13 . The nucleobase oligomer of  claim 12 , wherein said DNA residues are flanked on each side by at least three 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         14 . The nucleobase oligomer of  claim 13 , wherein said DNA residues are flanked on each side by four 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         15 . The nucleobase oligomer of  claim 12 , wherein said RNA residues are linked together by phosphorothioate linkages, and said RNA residues are linked to said DAN residues by phosphorothioate linkages.  
     
     
         16 . The nucleobase oligomer of  claim 11 , wherein said nucleobase oligomer comprises DNA residues linked together by phosphodiester linkages, said DNA residues flanked on each side by at least two 2′-O-methyl or 2′-O-methoxyethyl RNA residues linked together by phosphorothioate linkages.  
     
     
         17 . The nucleobase oligomer of  claim 16 , wherein said DNA residues are flanked on each side by at least three 2′-O-methyl or 2′-O-methoxyethyl RNA residues.  
     
     
         18 . The nucleobase oligomer of  claim 1 , said nucleobase oligimer comprising eleven DNA residues flanked on each side by four 2′-O-methyl RNA residues, said nucleobase oligomer consisting of SEQ ID NO: 97, said residues linked together by phosphorothioate linkages.  
     
     
         19 . The nucleobase oligomer of  claim 1 , wherein said nucleobase oligomer inhibits the expression of an IAP in said cell.  
     
     
         20 . A pharmaceutical composition comprising (i) a nucleobase oligomer of up to 30 nucleobases in length, said nucleobase oligomer comprising at least eight consecutive nucleobases of SEQ ID NO: 97; and (ii) a pharmaceutically acceptable carrier.  
     
     
         21 . The pharmaceutical composition of  claim 20 , further comprising a colloidal dispersion system.  
     
     
         22 . A catalytic RNA molecule capable of cleaving XIAP, HIAP1, or HIAP2 Mrna, the binding arms of which contain at least eight consecutive nucleobases of SEQ ID NO: 97.  
     
     
         23 . The catalytic RNA molecule of  claim 22 , wherein said RNA molecule is in a hammerhead motif.  
     
     
         24 . The catalytic RNA molecule of  claim 23 , wherein said RNA molecule is in a hairpin, hepatitis delta virus, group 1 intron, VS RNA or RNAseP RNA motif.  
     
     
         25 . An expression vector comprising a nucleic acid encoding a catalytic RNA molecule, the binding arms of which contain at least eight consecutive nucleobases of SEQ ID NO: 97, said nucleic acid positioned for expression in a mammalian cell.  
     
     
         26 . A double-stranded RNA molecule comprising between 21 and 29 nucleobases, said RNA molecule comprising at least eight consecutive nucleobases of SEQ ID NO: 97.  
     
     
         27 . A double-stranded RNA molecule comprising between 50 and 70 nucleobases, said RNA molecule comprising a first domain of between 21 and 29 nucleobases that comprise least eight consecutive nucleobases of SEQ ID NO: 97; a second domain complementary to said first domain, and a loop domain situated between said first and said second domains.  
     
     
         28 . An expression vector comprising a nucleic acid molecule encoding a double stranded RNA molecule comprising between 50 and 70 nucleobases, said RNA molecule comprising a first domain of between 21 and 29 nucleobases that comprise least eight consecutive nucleobases of SEQ ID NO :97; a second domain complementary to said first domain, and a loop domain situated between said first and said second domains, said nucleic acid positioned for expression in a mammalian cell.  
     
     
         29 . An oligonucleotide consisting of a sequence of SEQ ID NO 97.