MODIFIED OLIGONUCLEOTIDES FOR TELOMERASE INHIBITION
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 .