Modified oligonucleotides for telomerase inhibition

Abstract

Compounds comprising an oligonucleotide moiety covalently linked to a lipid moiety are disclosed. The oligonucleotide moiety comprises a sequence that is complementary to the RNA component of human telomerase. The compounds inhibit telomerase activity in cells with a high potency and have superior cellular uptake characteristics.

1 - 25 . (canceled) 
     
     
         26 . A method of modulating telomere length of a mammalian chromosome comprising contacting a mammalian chromosome with a chemically modified oligonucleotide having no more than 27 nucleic acid base units, said oligonucleotide having the sequence (N x (G 3-4 ) Q N x  wherein each X is independently 1 to 8 and Q is 1 to 6, wherein said oligonucleotide modulates mammalian telomere length. 
     
     
         27 . The method of  claim 26  which is carried out in vitro. 
     
     
         28 . The method of  claim 26  which is carried out in vivo. 
     
     
         29 . The method of  claim 26  wherein the oligonucleotide chemical modifications are selected from the group consisting of a modified internucleoside linkage, a modified sugar and a modified base. 
     
     
         30 . A method for inhibiting the division of a malignant mammalian cell comprising contacting said malignant mammalian cell with a chemically modified oligonucleotide having no more than 27 nucleic acid base units, said oligonucleotide having the sequence (N x G 3-4 ) Q N x  wherein each X is independently 1 to 8 and Q is 1 to 6, wherein said oligonucleotide modulates mammalian telomere length. 
     
     
         31 . The method of  claim 30  which is carried out in vitro. 
     
     
         32 . The method of  claim 30  which is carried out in vivo. 
     
     
         33 . The method of  claim 30  wherein the oligonucleotide chemical modifications are selected from the group consisting of a modified internucleoside linkage, a modified sugar and a modified base. 
     
     
         34 . A method for inhibiting the division of a malignant mammalian cell comprising contacting said malignant mammalian cell with a chemically modified oligonucleotide having no more than 27 nucleic acid base units, said oligonucleotide comprising the sequence (N x G 3-4 ) Q N x  wherein X is 1 to 8 and Q is 1 to 6, wherein said oligonucleotide modulates mammalian telomere length. 
     
     
         35 . The method of  claim 34  which is carried out in vitro. 
     
     
         36 . The method of  claim 34  which is carried out in vivo. 
     
     
         37 . The method of  claim 34  wherein the oligonucleotide chemical modifications are selected from the group consisting of a modified internucleoside linkage, a modified sugar and a modified base. 
     
     
         38 . An oligonucleotide comprising up to 24 nucleic acid base units and comprising the nucleotide sequence (N x G 3-4 ) Q N x , where N is any nucleotide, each X is, independently, 1-8, Q is 1-6, and comprising a modified intersugar linkage. 
     
     
         39 . An oligonucleotide of  claim 38  wherein the modified intersugar linkage of the oligonucleotide is thionophosphoramidate. 
     
     
         40 . An oligonucleotide of  claim 38  wherein the oligonucleotide is conjugated to a lipid. 
     
     
         41 . An oligonucleotide of  claim 38  wherein the oligonucleotide is conjugated to a palmityl moiety. 
     
     
         42 . An oligonucleotide of  claim 38  wherein in the oligonucleotide comprising the nucleotide sequence (N x G 3-4 ) Q N x , Q is 1. 
     
     
         43 . An oligonucleotide of  claim 38  wherein the oligonucleotide comprising the nucleotide sequence (N x G 3-4 ) Q N x  comprises 13 nucleic acid base units. 
     
     
         44 . An oligonucleotide of  claim 38  wherein the oligonucleotide comprising the nucleotide sequence (N x G 3-4 ) Q N x  comprises TAGGGT. 
     
     
         45 . An oligonucleotide comprising 13 nucleic acid base units and comprising the nucleotide sequence (N x G 3-4 ) Q N x , where N is any nucleotide, each X is, independently, 1-8, and Q is 1, wherein the backbone of the oligonucleotide is thionophosphoramidate, and wherein the oligonucleotide is conjugated to a lipid. 
     
     
         46 . An oligonucleotide of  claim 45  wherein the lipid is a palmityl moiety. 
     
     
         47 . An oligonucleotide of  claim 45  wherein the oligonucleotide comprising the nucleotide sequence (N x G 3-4 ) Q N x  comprises TAGGGT. 
     
     
         48 . A composition comprising the oligonucleotide of  claim 38 . 
     
     
         49 . A composition comprising the oligonucleotide of  claim 45 .