MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING MYOTONIC DYSTROPHY
The present application relates to oligonucleotides (e.g., antisense oligonucleotides such as gapmers) designed to target DMPK RNAs and targeting complexes for delivering the oligonucleotides to cells (e.g., muscle cells) and uses thereof, particularly uses relating to treatment of disease. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of DMPK.
1 . A complex comprising an anti-transferrin receptor 1 (TfR1) antibody covalently linked to an oligonucleotide configured for reducing expression or activity of DMPK, wherein the anti-TfR1 antibody comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3) of a heavy chain variable region (VH) comprising the amino acid sequence SEQ ID NO: 72, and a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3) of a light chain variable region (VL) comprising the amino acid sequence SEQ ID NO: 70,
and wherein the oligonucleotide comprises a 5′-X-Y-Z-3′ configuration, wherein
X comprises 3-7 linked nucleosides, wherein at least one of the nucleosides in X is a 2′-modified nucleoside;
Y comprises 6-15 linked 2′-deoxyribonucleosides, wherein each cytosine in Y is optionally and independently a 5-methyl-cytosine; and
Z comprises 3-7 linked nucleosides, wherein at least one of the nucleosides in Z is a 2′-modified nucleoside; and
wherein the oligonucleotide comprises a region of complementarity to at least 15 consecutive nucleosides of any one of SEQ ID NOs: 205, 214, 222, 217, 211, 215, 220, 225, 160-204, 206-210, 212, 213, 216, 218, 219, 221, 223, 224, and 226-230.
2 . The complex of claim 1 , wherein
X comprises 3-5 linked nucleosides, wherein at least one of the nucleosides in X is a 2′-modified nucleoside;
Y comprises 6-10 linked 2′-deoxyribonucleosides, wherein each cytosine in Y is optionally and independently a 5-methyl-cytosine; and
Z comprises 3-5 linked nucleosides, wherein at least one of the nucleosides in Z is a 2′-modified nucleoside.
3 .- 4 . (canceled)
5 . The complex of claim 1 , wherein the antibody and the oligonucleotide are covalently linked via a cleavable linker, optionally wherein the cleavable linker comprises a valine-citrulline sequence.
6 . The complex of claim 1 , wherein the oligonucleotide is 15 to 25 nucleosides in length, optionally wherein the oligonucleotide is 15 to 20 nucleosides in length.
7 . The complex of claim 1 , wherein the oligonucleotide comprises at least 15 consecutive nucleosides of any one of SEQ ID NOs: 276, 348, 354, 350, 345, 286, 352, 357, 231-275, 277-285, 287-344, 346, 347, 349, 351, 353, 355, 356, and 358-362, wherein each thymine base (T) may independently and optionally be replaced with a uracil base (U), and each U may independently and optionally be replaced with a T.
8 . The complex of claim 1 , wherein each nucleoside in X is a 2′-modified nucleoside and/or each nucleoside in Z is a 2′-modified nucleoside, optionally wherein each 2′-modified nucleoside is independently a 2′-4′ bicyclic nucleoside or a non-bicyclic 2′-modified nucleoside.
9 . The complex of claim 1 , wherein the oligonucleotide comprises a 5′-X-Y-Z-3′ configuration of:
X
Y
Z
EEEEE
(D) 10
EEEEE,
EEF
(D) 10
EEE,
EEEEE
(D) 10
EEEE,
EEEEE
(D) 10
EE,
LLL
(D) 10
LLL,
EELL
(D) 8
LLEE,
LLEE
(D) 8
EELL, or
LLEEE
(D) 10
EEELL,
wherein “E” is a 2′-MOE modified ribonucleoside; “L” is LNA; “D” is 2′-deoxyribonucleoside; and “10” or “8” is the number of the 2′-deoxyribonucleosides in Y.
10 . The complex of claim 1 , wherein the oligonucleotide comprises one or more phosphorothioate internucleoside linkages, optionally wherein each internucleoside linkage in the oligonucleotide is a phosphorothioate internucleoside linkage.
11 . (canceled)
12 . The complex of claim 1 , wherein the oligonucleotide comprises one or more phosphodiester internucleoside linkages, optionally wherein the one or more phosphodiester internucleoside linkages are in X and/or Z.
13 . The complex of claim 1 , wherein the oligonucleotide comprises a structure selected from:
(SEQ ID NO: 302)
oC*oA*oU*oG*oG*dC*dA*dT*dA*dC*dA*dC*dC*dT*dG*oG*oC*oC*oC*oG,
(SEQ ID NO: 303)
oC*oA*oC*oC*oA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*dT*oC*oU*oC*C*oU,
(SEQ ID NO: 304)
oU*oC*oA*oC*oC*dA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*oU*oC*oU*oC*oC,
(SEQ ID NO: 305)
oC*oC*oA*oU*oU*dC*dA*dC*dC*dA*dA*dC*dA*xdC*dG*oU*oC*C*oC*oU,
(SEQ ID NO: 306)
oU*oA*oC*oA*oG*dG*dT*dA*dG*dT*dT*dC*dT*dC*dA*oU*oC*oC*oU*oG,
(SEQ ID NO: 307)
oG*oU*oA*oC*oA*dG*dG*dT*dA*dG*dT*dT*dC*dT*dC*oA*oU*oC*oC*oU,
(SEQ ID NO: 308)
oA*oC*oC*oA*oG*dG*dT*dA*dC*dA*dG*dG*dT*dA*dG*oU*oU*oC*oU*oC,
(SEQ ID NO: 309)
oG*oA*oC*oC*oA*dG*dG*dT*dA*dC*dA*dG*dG*dT*dA*oG*oU*oU*oC*oU,
(SEQ ID NO: 310)
oU*oG*oA*C*oC*dA*dG*dG*dT*dA*dC*dA*dG*dG*dT*oA*xoG*oU*oU*oC,
(SEQ ID NO: 311)
oC*oC*oC*oA*oA*dA*dC*dT*dT*dG*dC*dT*dC*dA*dG*oC*oA*oG*oU*oG,
(SEQ ID NO: 312)
oU*oG*oA*oC*oA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*dA*oG*oG*oU*oA*oG,
(SEQ ID NO: 313)
oA*oU*oG*oA*oC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*oA*oG*oG*oU*oA,
(SEQ ID NO: 314)
oC*oA*oU*oG*oA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*oC*oA*oG*oG*oU,
(SEQ ID NO: 315)
oC*oC*oA*oU*oG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*oC*oC*oA*oG*oG,
(SEQ ID NO: 316)
oG*oC*oC*oA*oU*dG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*oG*oC*oC*oA*oG,
(SEQ ID NO: 246)
oG*oG*oC*oC*oA*dT*dG*dA*dC*dA*dA*dT*dC*dT*dC*oC*oG*oC*oC*oA,
(SEQ ID NO: 317)
oU*oG*oG*oC*oC*dA*dT*dG*dA*dC*dA*dA*dT*dC*dT*oC*oC*oG*oC*oC,
(SEQ ID NO: 318)
oU*oG*oU*oG*oC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*dA*oG*oC*oC*oG*oG,
(SEQ ID NO: 319)
oC*oU*oG*oU*oG*dC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*oA*oG*oC*oC*oG,
(SEQ ID NO: 320)
oC*oA*oC*oA*oG*xdC*dG*dG*dT*dC*dC*dA*dG*dC*dA*oG*oG*oA*oU*oG,
(SEQ ID NO: 321)
oU*oG*oG*oC*oC*dA*dC*dA*dG*xdC*dG*dG*dT*dC*dC*oA*oG*oC*oA*oG,
(SEQ ID NO: 322)
oA*oG*oC*oG*oC*dC*dC*dA*dC*dC*dA*dG*dT*dC*dA*oC*oA*oC*oU*oC,
(SEQ ID NO: 323)
oC*oA*oG*oC*oG*dC*dC*dC*dA*dC*dC*dA*dG*dT*dC*oA*oC*oA*oC*oU,
(SEQ ID NO: 254)
oC*oC*oA*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*dG*dT*oC*oA*oC*oA*oC,
(SEQ ID NO: 255)
oG*oC*oG*oA*oA*dT*dA*dC*dA*dC*dC*dC*dA*dG*xdC*oG*oC*oC*oC*oA,
(SEQ ID NO: 256)
oG*oG*oC*oG*oA*dA*dT*dA*dC*dA*dC*dC*dC*dA*dG*oC*oG*oC*oC*oC,
(SEQ ID NO: 324)
oU*oU*oG*oU*oA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*dC*oU*oU*oG*oC*oC,
(SEQ ID NO: 325)
oC*oU*oU*oG*oU*dA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*oC*oU*oU*oG*oC,
(SEQ ID NO: 326)
oC*oC*oU*oU*oG*dT*dA*dG*dT*dG*dG*dA*xdC*dG*dA*oU*oC*oU*oU*oG,
(SEQ ID NO: 327)
oC*oG*oG*oA*oG*dA*dC*dC*dA*dT*dC*dC*dC*dA*dG*oU*oC*oG*oA*oG,
(SEQ ID NO: 328)
oG*oA*oA*oU*oG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*dG*oU*oC*oU*oC*oC,
(SEQ ID NO: 329)
*oG*oA*oA*oU*dG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*oG*oU*oC*oU*oC,
(SEQ ID NO: 330)
oG*oG*oG*oC*oC*dT*dG*dG*dG*dA*dC*dC*dT*dC*dA*oC*oU*oG*oU*oC,
(SEQ ID NO: 331)
oU*oG*oC*oA*oC*dG*dT*dG*dT*dG*dG*dC*dT*dC*dA*oA*oG*oC*oA*oG,
(SEQ ID NO: 332)
oC*oC*oA*oC*oU*dT*dC*dA*dG*dC*dT*dG*dT*dT*dT*oC*oA*oU*oC*oC,
(SEQ ID NO: 333)
oG*oC*oG*oU*oC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*dT*oC*oA*oG*oC*oC,
(SEQ ID NO: 334)
oA*oG*oC*oG*oU*dC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*oU*oC*oA*oG*oC,
(SEQ ID NO: 335)
oC*oG*oU*oA*oG*dT*dT*dG*dA*dC*dT*dG*dG*xdC*dG*oA*oA*oG*oU*oU,
(SEQ ID NO: 336)
oG*oG*oG*oC*C*xdC*dG*dG*dA*dT*dC*dA*dC*dA*dG*oG*oA*oC*oU*oG,
(SEQ ID NO: 337)
-oU*oU*oG*oC*oC*dC*dA*dT*dC*dC*dA*xdC*dG*dT*dC*oA*oG*oG*oG*oC,
(SEQ ID NO: 338)
oG*oG*oA*oC*oG*dG*dC*dC*xdC*dG*dG*dC*dT*dT*dG*oC*oU*oG*oC*oC,
(SEQ ID NO: 339)
oU*oG*oG*oA*oA*dC*dA*xdC*dG*dG*dA*xdC*dG*dG*dC*oC*oC*oG*oG*oC,
(SEQ ID NO: 340)
oC*oA*oU*oC*oC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*dA*oU*oU*oG*oG*oG,
and
(SEQ ID NO: 341)
oG*oC*oA*oU*oC*dC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*oA*oU*oU*oG*oG,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “oC” is 5-methyl-2′-MOE-cytidine; “oU” is 5-methyl-2′-MOE-uridine; “xoG” is 7-methyl-2′-MOE-guanosine; and “*” indicates a phosphorothioate (PS) internucleoside linkage.
14 . The complex of claim 13 , wherein the oligonucleotide is conjugated to an amine group at its 5′-end and comprises a structure selected from:
(SEQ ID NO: 302)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oG*oG*dC*dA*dT*dA*dC*dA*dC*dC*dT*dG*oG*oC*oC*oC*oG,
(SEQ ID NO: 303)
NH 2 -(CH 2 ) 6 -oC*oA*oC*oC*oA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*dT*oC*oU*oC*C*oU,
(SEQ ID NO: 304)
NH 2 -(CH 2 ) 6 -oU*oC*oA*oC*oC*dA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*oU*oC*oU*oC*oC,
(SEQ ID NO: 305)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oU*oU*dC*dA*dC*dC*dA*dA*dC*dA*xdC*dG*oU*oC*C*oC*oU,
(SEQ ID NO: 306)
NH 2 -(CH 2 ) 6 -oU*oA*oC*oA*oG*dG*dT*dA*dG*dT*dT*dC*dT*dC*dA*oU*oC*oC*oU*oG,
(SEQ ID NO: 307)
NH 2 -(CH 2 ) 6 -oG*oU*oA*oC*oA*dG*dG*dT*dA*dG*dT*dT*dC*dT*dC*oA*oU*oC*oC*oU,
(SEQ ID NO: 308)
NH 2 -(CH 2 ) 6 -oA*oC*oC*oA*oG*dG*dT*dA*dC*dA*dG*dG*dT*dA*dG*oU*oU*oC*oU*oC,
(SEQ ID NO: 309)
NH 2 -(CH 2 ) 6 -oG*oA*oC*oC*oA*dG*dG*dT*dA*dC*dA*dG*dG*dT*dA*oG*oU*oU*oC*oU,
(SEQ ID NO: 310)
NH 2 -(CH 2 ) 6 -oU*oG*oA*C*oC*dA*dG*dG*dT*dA*dC*dA*dG*dG*dT*oA*xoG*oU*oU*oC,
(SEQ ID NO: 311)
NH 2 -(CH 2 ) 6 -oC*oC*oC*oA*oA*dA*dC*dT*dT*dG*dC*dT*dC*dA*dG*oC*oA*oG*oU*oG,
(SEQ ID NO: 312)
NH 2 -(CH 2 ) 6 -oU*oG*oA*oC*oA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*dA*oG*oG*oU*oA*oG,
(SEQ ID NO: 313)
NH 2 -(CH 2 ) 6 -oA*oU*oG*oA*oC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*oA*oG*oG*oU*oA,
(SEQ ID NO: 314)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oG*oA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*oC*oA*oG*oG*oU,
(SEQ ID NO: 315)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oU*oG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*oC*oC*oA*oG*oG,
(SEQ ID NO: 316)
NH 2 -(CH 2 ) 6 -oG*oC*oC*oA*oU*dG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*oG*oC*oC*oA*oG,
(SEQ ID NO: 246)
NH 2 -(CH 2 ) 6 -oG*oG*oC*oC*oA*dT*dG*dA*dC*dA*dA*dT*dC*dT*dC*oC*oG*oC*oC*oA,
(SEQ ID NO: 317)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oC*oC*dA*dT*dG*dA*dC*dA*dA*dT*dC*dT*oC*oC*oG*oC*oC,
(SEQ ID NO: 318)
NH 2 -(CH 2 ) 6 -oU*oG*oU*oG*oC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*dA*oG*oC*oC*oG*oG,
(SEQ ID NO: 319)
NH 2 -(CH 2 ) 6 -oC*oU*oG*oU*oG*dC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*oA*oG*oC*oC*oG,
(SEQ ID NO: 320)
NH 2 -(CH 2 ) 6 -oC*oA*oC*oA*oG*xdC*dG*dG*dT*dC*dC*dA*dG*dC*dA*oG*oG*oA*oU*oG,
(SEQ ID NO: 321)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oC*oC*dA*dC*dA*dG*xdC*dG*dG*dT*dC*dC*oA*oG*oC*oA*oG,
(SEQ ID NO: 322)
NH 2 -(CH 2 ) 6 -oA*oG*oC*oG*oC*dC*dC*dA*dC*dC*dA*dG*dT*dC*dA*oC*oA*oC*oU*oC,
(SEQ ID NO: 323)
NH 2 -(CH 2 ) 6 -oC*oA*oG*oC*oG*dC*dC*dC*dA*dC*dC*dA*dG*dT*dC*oA*oC*oA*oC*oU,
(SEQ ID NO: 254)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*dG*dT*oC*oA*oC*oA*oC,
(SEQ ID NO: 255)
NH 2 -(CH 2 ) 6 -oG*oC*oG*oA*oA*dT*dA*dC*dA*dC*dC*dC*dA*dG*xdC*oG*oC*oC*oC*oA,
(SEQ ID NO: 256)
NH 2 -(CH 2 ) 6 -oG*oG*oC*oG*oA*dA*dT*dA*dC*dA*dC*dC*dC*dA*dG*oC*oG*oC*oC*oC,
(SEQ ID NO: 324)
NH 2 -(CH 2 ) 6 -oU*oU*oG*oU*oA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*dC*oU*oU*oG*oC*oC,
(SEQ ID NO: 325)
NH 2 -(CH 2 ) 6 -oC*oU*oU*oG*oU*dA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*oC*oU*oU*oG*oC,
(SEQ ID NO: 326)
NH 2 -(CH 2 ) 6 -oC*oC*oU*oU*oG*dT*dA*dG*dT*dG*dG*dA*xdC*dG*dA*oU*oC*oU*oU*oG,
(SEQ ID NO: 327)
NH 2 -(CH 2 ) 6 -oC*oG*oG*oA*oG*dA*dC*dC*dA*dT*dC*dC*dC*dA*dG*oU*oC*oG*oA*oG,
(SEQ ID NO: 328)
NH 2 -(CH 2 ) 6 -oG*oA*oA*oU*oG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*dG*oU*oC*oU*oC*oC,
(SEQ ID NO: 329)
NH 2 -(CH 2 ) 6 -oC*oG*oA*oA*oU*dG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*oG*oU*oC*oU*oC,
(SEQ ID NO: 330)
NH 2 -(CH 2 ) 6 -oG*oG*oG*oC*oC*dT*dG*dG*dG*dA*dC*dC*dT*dC*dA*oC*oU*oG*oU*oC,
(SEQ ID NO: 331)
NH 2 -(CH 2 ) 6 -oU*oG*oC*oA*oC*dG*dT*dG*dT*dG*dG*dC*dT*dC*dA*oA*oG*oC*oA*oG,
(SEQ ID NO: 332)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oC*oU*dT*dC*dA*dG*dC*dT*dG*dT*dT*dT*oC*oA*oU*oC*oC,
(SEQ ID NO: 333)
NH 2 -(CH 2 ) 6 -oG*oC*oG*oU*oC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*dT*oC*oA*oG*oC*oC,
(SEQ ID NO: 334)
NH 2 -(CH 2 ) 6 -oA*oG*oC*oG*oU*dC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*oU*oC*oA*oG*oC,
(SEQ ID NO: 335)
NH 2 -(CH 2 ) 6 -oC*oG*oU*oA*oG*dT*dT*dG*dA*dC*dT*dG*dG*xdC*dG*oA*oA*oG*oU*oU,
(SEQ ID NO: 336)
NH 2 -(CH 2 ) 6 -oG*oG*oG*oC*C*xdC*dG*dG*dA*dT*dC*dA*dC*dA*dG*oG*oA*oC*oU*oG,
(SEQ ID NO: 337)
NH 2 -(CH 2 ) 6 -oU*oU*oG*oC*oC*dC*dA*dT*dC*dC*dA*xdC*dG*dT*dC*oA*oG*oG*oG*oC,
(SEQ ID NO: 338)
NH 2 -(CH 2 ) 6 -oG*oG*oA*oC*oG*dG*dC*dC*xdC*dG*dG*dC*dT*dT*dG*oC*oU*oG*oC*oC,
(SEQ ID NO: 339)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oA*oA*dC*dA*xdC*dG*dG*dA*xdC*dG*dG*dC*oC*oC*oG*oG*oC,
(SEQ ID NO: 340)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oC*oC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*dA*oU*oU*oG*oG*oG,
and
(SEQ ID NO: 341)
NH 2 -(CH 2 ) 6 -oG*oC*oA*oU*oC*dC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*oA*oU*oU*oG*oG,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “oC” is 5-methyl-2′-MOE-cytidine; “oU” is 5-methyl-2′-MOE-uridine; “xoG” is 7-methyl-2′-MOE-guanosine; and “*” indicates a phosphorothioate (PS) internucleoside linkage,
and optionally wherein a phosphodiester linkage or other moiety is present between the 5′-NH 2 —(CH 2 ) 6 — and the oligonucleotide.
15 . The complex of claim 1 , wherein the oligonucleotide comprises a structure selected from:
(SEQ ID NO: 276)
+G*x+C*oA*xoC*dG*dT*dG*dT*dG*dG*xdC*dT*xoC*oA*+A*+G,
(SEQ ID NO: 348)
+A*x+C*xoC*oA*dA*xdC*dA*xdC*dG*dT*xdC*xdC*xoC*oU*x+C*+U,
(SEQ ID NO: 354)
x+C*x+C*xoC*oG*dG*dA*dT*xdC*dA*xdC*dA*dG*oG*oA*x+C*+U,
(SEQ ID NO: 350)
+G*+U*oA*oG*dT*dT*dG*dA*xdC*dT*dG*dG*xoC*oG*+A*+A,
(SEQ ID NO: 345)
x+C*+A*oU*oG*dA*xdC*dA*dA*dT*xdC*dT*xdC*xoC*oG*x+C*x+C,
(SEQ ID NO: 286)
xoC*xoC*+A*+A*dA*xdC*dT*dT*dG*xdC*dT*xdC*+A*+G*xoC*oA,
(SEQ ID NO: 352)
xoC*oU*+U*x+C*dA*dG*xdC*dT*dG*dT*dT*dT*x+C*+A*oU*xoC,
(SEQ ID NO: 357)
x+C*+G*oU*xoC*dA*xdC*xdC*dT*xdC*dG*dG*xdC*xoC*oU*x+C*+A,
(SEQ ID NO: 275)
x+C*+A*xoC*oG*dT*dG*dT*dG*dG*xdC*dT*xdC*oA*oA*+G*x+C,
(SEQ ID NO: 275)
xoC*oA*x+C*+G*dT*dG*dT*dG*dG*xdC*dT*xdC*+A*+A*oG*xoC,
(SEQ ID NO: 276)
oG*xoC*+A*x+C*dG*dT*dG*dT*dG*dG*xdC*dT*x+C*+A*oA*oG,
(SEQ ID NO: 342)
+A*x+C*oG*oU*dG*dT*dG*dG*xdC*dT*xdC*dA*oA*oG*x+C*+A,
(SEQ ID NO: 342)
oA*xoC*+G*+U*dG*dT*dG*dG*xdC*dT*xdC*dA*+A*+G*xoC*oA,
(SEQ ID NO: 278)
x+C*+A*oA*oA*xdC*dT*dT*dG*xdC*dT*xdC*dA*oG*xoC*+A*+G,
(SEQ ID NO: 343)
+A*x+C*oU*oU*xdC*dA*dG*xdC*dT*dG*dT*dT*oU*xoC*+A*+U,
(SEQ ID NO: 344)
+U*+A*oG*oU*dT*dG*dA*xdC*dT*dG*dG*xdC*oG*A*+A*+G,
(SEQ ID NO: 281)
+G*x+C*xoC*xoC*dG*dG*dA*dT*dC*dA*xdC*dA*oG*oG*+A*x+C,
(SEQ ID NO: 346)
+G*+U*xoC*oA*xdC*xdC*dT*xdC*dG*dG*xdC*dC*oU*xoC*+A*+G,
(SEQ ID NO: 347)
x+C*x+C*A*oG*dG*dT*dA*xdC*dA*dG*dG*dT*oA*oG*+U*+U,
(SEQ ID NO: 286)
x+C*x+C*oA*oA*dA*xdC*dT*dT*dG*xdC*dT*xdC*oA*oG*x+C*+A,
(SEQ ID NO: 349)
x+C*+A*xoC*oU*dT*xdC*dA*dG*xdC*dT*dG*dT*oU*oU*x+C*+A,
(SEQ ID NO: 289)
+G*+G*xoC*xoC*xdC*dG*dG*dA*dT*xdC*dA*xdC*oA*oG*+G*+A,
(SEQ ID NO: 351)
+A*+A*oA*xoC*dT*dT*dG*xdC*dT*xdC*dA*dG*xoC*oA*+G*+U,
(SEQ ID NO: 352)
x+C*+U*oU*xoC*dA*dG*xdC*dT*dG*dT*dT*dT*xoC*oA*+U*x+C,
(SEQ ID NO: 353)
+A*+G*oU*oU*dG*dA*xdC*dT*dG*dG*xdC*dG*oA*oA*+G*+U,
(SEQ ID NO: 278)
XoC*oA*+A*+A*xdC*dT*dT*dG*xdC*dT*xdC*dA*+G*x+C*oA*oG,
(SEQ ID NO: 343)
oA*xoC*+U*+U*xdC*dA*dG*xdC*dT*dG*dT*dT*+U*x+C*oA*oU,
(SEQ ID NO: 344)
oU*oA*+G*+U*dT*dG*dA*xdC*dT*dG*dG*xdC*+G*+A*oA*oG,
(SEQ ID NO: 281)
oG*xoC*x+C*x+C*dG*dG*dA*dT*dC*dA*dC*dA*+G*+G*oA*xoC,
(SEQ ID NO: 349)
xoC*oA*x+C*+U*dT*xdC*dA*dG*xdC*dT*dG*dT*+U*+U*xoC*oA,
(SEQ ID NO: 350)
oG*oU*+A*+G*dT*dT*dG*dA*xdC*dT*dG*dG*x+C*+G*oA*oA,
(SEQ ID NO: 289)
oG*oG*x+C*x+C*xdC*G*dG*dA*dT*xdC*dA*xdC*+A*+G*oG*oA,
(SEQ ID NO: 351)
oA*oA*+A*x+C*dT*dT*dG*xdC*dT*xdC*dA*dG*x+C*+A*oG*oU,
(SEQ ID NO: 353)
oA*oG*+U*+U*dG*dA*xdC*dT*dG*dG*xdC*dG*+A*+A*oG*oU,
(SEQ ID NO: 354)
xoC*xoC*x+C*+G*dG*dA*dT*xdC*dA*xdC*dA*dG*+G*+A*xoC*oU,
(SEQ ID NO: 355)
x+C*x+C*A*oU*dG*dA*xdC*dA*dA*dT*xdC*dT*xoC*xoC*+G*x+C,
(SEQ ID NO: 356)
+A*+U*G*oA*xdC*dA*dA*dT*xdC*dT*xdC*xdC*oG*xoC*x+C*+A,
(SEQ ID NO: 358)
+U*x+C*oA*xoC*xdC*dT*xdC*dG*dG*xdC*xdC*dT*xoC*oA*+G*x+C,
(SEQ ID NO: 359)
+A*x+C*xoC*oA*dG*dG*dT*dA*xdC*dA*dG*dG*oU*oA*+G*+U,
(SEQ ID NO: 360)
x+C*+A*oG*oG*dT*dA*xdC*dA*dG*dG*dT*dA*oG*oU*+U*x+C,
(SEQ ID NO: 361)
x+C*+A*xoC*xoC*dA*dA*xdC*dA*xdC*dG*dT*xdC*xoC*xoC*+U*x+C,
and
(SEQ ID NO: 362)
x+C*x+C*oA*oA*xdC*dA*xdC*dG*dT*xdC*xdC*xdC*oU*xoC*+U*x+C,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “xoC” is 5-methyl-2′-MOE-cytidine; “x+C” is 5-methyl LNA cytidine; “+N” is an LNA nucleoside; “oU” is 5-methyl-2′-MOE-uridine; “+U” is 5-methyl LNA uridine; and “*” indicates a phosphorothioate (PS) internucleoside linkage.
16 . The complex of claim 15 , wherein the oligonucleotide is conjugated to an amine group at its 5′-end and comprises a structure selected from:
(SEQ ID NO: 276)
NH 2 -(CH 2 ) 6 -+G*x+C*oA*xoC*dG*dT*dG*dT*dG*dG*xdC*dT*xoC*oA*+A*+G,
(SEQ ID NO: 348)
NH 2 -(CH 2 ) 6 -+A*x+C*xoC*oA*dA*xdC*dA*xdC*dG*dT*xdC*xdC*xoC*oU*x+C*+U,
(SEQ ID NO: 354)
NH 2 -(CH 2 ) 6 -x+C*x+C*xoC*oG*dG*dA*dT*xdC*dA*xdC*dA*dG*oG*oA*x+C*+U,
(SEQ ID NO: 350)
NH 2 -(CH 2 ) 6 -+G*+U*oA*oG*dT*dT*dG*dA*xdC*dT*dG*dG*xoC*oG*+A*+A,
(SEQ ID NO: 345)
NH 2 -(CH 2 ) 6 -x+C*+A*oU*oG*dA*xdC*dA*dA*dT*xdC*dT*xdC*xoC*oG*x+C*x+C,
(SEQ ID NO: 286)
NH 2 -(CH 2 ) 6 -xoC*xoC*+A*+A*dA*xdC*dT*dT*dG*xdC*dT*xdC*+A*+G*xoC*oA,
(SEQ ID NO: 352)
NH 2 -(CH 2 ) 6 -xoC*oU*+U*x+C*dA*dG*xdC*dT*dG*dT*dT*dT*x+C*+A*oU*xoC,
(SEQ ID NO: 357)
NH 2 -(CH 2 ) 6 -x+C*+G*oU*xoC*dA*xdC*xdC*dT*xdC*dG*dG*xdC*xoC*oU*x+C*+A,
(SEQ ID NO: 275)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*oG*dT*dG*dT*dG*dG*xdC*dT*xdC*oA*oA*+G*x+C,
(SEQ ID NO: 275)
NH 2 -(CH 2 ) 6 -xoC*oA*x+C*+G*dT*dG*dT*dG*dG*xdC*dT*xdC*+A*+A*oG*xoC,
(SEQ ID NO: 276)
NH 2 -(CH 2 ) 6 -oG*xoC*+A*x+C*dG*dT*dG*dT*dG*dG*xdC*dT*x+C*+A*oA*oG,
(SEQ ID NO: 342)
NH 2 -(CH 2 ) 6 -+A*x+C*oG*oU*dG*dT*dG*dG*xdC*dT*xdC*dA*oA*oG*x+C*+A,
(SEQ ID NO: 342)
NH 2 -(CH 2 ) 6 -oA*xoC*+G*+U*dG*dT*dG*dG*xdC*dT*xdC*dA*+A*+G*xoC*oA,
(SEQ ID NO: 278)
NH 2 -(CH 2 ) 6 -x+C*+A*oA*oA*xdC*dT*dT*dG*xdC*dT*xdC*dA*oG*xoC*+A*+G,
(SEQ ID NO: 343)
NH 2 -(CH 2 ) 6 -+A*x+C*oU*oU*xdC*dA*dG*xdC*dT*dG*dT*dT*oU*xoC*+A*+U,
(SEQ ID NO: 344)
NH 2 -(CH 2 ) 6 -+U*+A*oG*oU*dT*dG*dA*xdC*dT*dG*dG*xdC*oG*A*+A*+G,
(SEQ ID NO: 281)
NH 2 -(CH 2 ) 6 -+G*x+C*xoC*xoC*dG*dG*dA*dT*dC*dA*xdC*dA*oG*oG*+A*x+C,
(SEQ ID NO: 346)
NH 2 -(CH 2 ) 6 -+G*+U*xoC*oA*xdC*xdC*dT*xdC*dG*dG*xdC*dC*oU*xoC*+A*+G,
(SEQ ID NO: 347)
NH 2 -(CH 2 ) 6 -x+C*x+C*A*oG*dG*dT*dA*xdC*dA*dG*dG*dT*oA*oG*+U*+U,
(SEQ ID NO: 286)
NH 2 -(CH 2 ) 6 -x+C*x+C*oA*oA*dA*xdC*dT*dT*dG*xdC*dT*xdC*oA*oG*x+C*+A,
(SEQ ID NO: 349)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*oU*dT*xdC*dA*dG*xdC*dT*dG*dT*oU*oU*x+C*+A,
(SEQ ID NO: 289)
NH 2 -(CH 2 ) 6 -+G*+G*xoC*xoC*xdC*dG*dG*dA*dT*xdC*dA*xdC*oA*oG*+G*+A,
(SEQ ID NO: 351)
NH 2 -(CH 2 ) 6 -+A*+A*oA*xoC*dT*dT*dG*xdC*dT*xdC*dA*dG*xoC*oA*+G*+U,
(SEQ ID NO: 352)
NH 2 -(CH 2 ) 6 -x+C*+U*oU*xoC*dA*dG*xdC*dT*dG*dT*dT*dT*xoC*oA*+U*x+C,
(SEQ ID NO: 353)
NH 2 -(CH 2 ) 6 -+A*+G*oU*oU*dG*dA*xdC*dT*dG*dG*xdC*dG*oA*oA*+G*+U,
(SEQ ID NO: 278)
NH 2 -(CH 2 ) 6 -XoC*oA*+A*+A*xdC*dT*dT*dG*xdC*dT*xdC*dA*+G*x+C*oA*oG,
(SEQ ID NO: 343)
NH 2 -(CH 2 ) 6 -oA*xoC*+U*+U*xdC*dA*dG*xdC*dT*dG*dT*dT*+U*x+C*oA*oU,
(SEQ ID NO: 344)
NH 2 -(CH 2 ) 6 -oU*oA*+G*+U*dT*dG*dA*xdC*dT*dG*dG*xdC*+G*+A*oA*oG,
(SEQ ID NO: 281)
NH 2 -(CH 2 ) 6 -oG*xoC*x+C*x+C*dG*dG*dA*dT*dC*dA*dC*dA*+G*+G*oA*xoC,
(SEQ ID NO: 349)
NH 2 -(CH 2 ) 6 -xoC*oA*x+C*+U*dT*xdC*dA*dG*xdC*dT*dG*dT*+U*+U*xoC*oA,
(SEQ ID NO: 350)
NH 2 -(CH 2 ) 6 -oG*oU*+A*+G*dT*dT*dG*dA*xdC*dT*dG*dG*x+C*+G*oA*oA,
(SEQ ID NO: 289)
NH 2 -(CH 2 ) 6 -oG*oG*x+C*x+C*xdC*G*dG*dA*dT*xdC*dA*xdC*+A*+G*oG*oA,
(SEQ ID NO: 351)
NH 2 -(CH 2 ) 6 -oA*oA*+A*x+C*dT*dT*dG*xdC*dT*xdC*dA*dG*x+C*+A*oG*oU,
(SEQ ID NO: 353)
NH 2 -(CH 2 ) 6 -oA*oG*+U*+U*dG*dA*xdC*dT*dG*dG*xdC*dG*+A*+A*oG*oU,
(SEQ ID NO: 354)
NH 2 -(CH 2 ) 6 -xoC*xoC*x+C*+G*dG*dA*dT*xdC*dA*xdC*dA*dG*+G*+A*xoC*oU,
(SEQ ID NO: 355)
NH 2 -(CH 2 ) 6 -x+C*x+C*A*oU*dG*dA*xdC*dA*dA*dT*xdC*dT*xoC*xoC*+G*x+C,
(SEQ ID NO: 356)
NH 2 -(CH 2 ) 6 -+A*+U*G*oA*xdC*dA*dA*dT*xdC*dT*xdC*xdC*oG*xoC*x+C*+A,
(SEQ ID NO: 358)
NH 2 -(CH 2 ) 6 -+U*x+C*oA*xoC*xdC*dT*xdC*dG*dG*xdC*xdC*dT*xoC*oA*+G*x+C,
(SEQ ID NO: 359)
NH 2 -(CH 2 ) 6 -+A*x+C*xoC*oA*dG*dG*dT*dA*xdC*dA*dG*dG*oU*oA*+G*+U,
(SEQ ID NO: 360)
NH 2 -(CH 2 ) 6 -x+C*+A*oG*oG*dT*dA*xdC*dA*dG*dG*dT*dA*oG*oU*+U*x+C,
(SEQ ID NO: 361)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*xoC*dA*dA*xdC*dA*xdC*dG*dT*xdC*xoC*xoC*+U*x+C,
and
(SEQ ID NO: 362)
NH 2 -(CH 2 ) 6 -x+C*x+C*oA*oA*xdC*dA*xdC*dG*dT*xdC*xdC*xdC*oU*xoC*+U*x+C,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “xoC” is 5-methyl-2′-MOE-cytidine; “x+C” is 5-methyl LNA cytidine; “+N” is an LNA nucleoside; “oU” is 5-methyl-2′-MOE-uridine; “+U” is 5-methyl LNA uridine; and “*” indicates a phosphorothioate (PS) internucleoside linkage,
and optionally wherein a phosphodiester linkage or other moiety is present between the 5′-NH 2 —(CH 2 ) 6 — and the oligonucleotide.
17 . A method of reducing DMPK expression in a muscle cell, the method comprising contacting the muscle cell with an effective amount of the complex of claim 1 to reduce DMPK expression in the muscle cell.
18 .- 19 . (canceled)
20 . A method of treating myotonic dystrophy type 1 (DM1), the method comprising administering to a subject in need thereof an effective amount of the complex of claim 1 .
21 .- 22 . (canceled)
23 . An oligonucleotide comprising a structure selected from:
(SEQ ID NO: 302)
oC*oA*oU*oG*oG*dC*dA*dT*dA*dC*dA*dC*dC*dT*dG*oG*oC*oC*oC*oG,
(SEQ ID NO: 303)
oC*oA*oC*oC*oA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*dT*oC*oU*oC*C*oU,
(SEQ ID NO: 304)
oU*oC*oA*oC*oC*dA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*oU*oC*oU*oC*oC,
(SEQ ID NO: 305)
oC*oC*oA*oU*oU*dC*dA*dC*dC*dA*dA*dC*dA*xdC*dG*oU*oC*C*oC*oU,
(SEQ ID NO: 306)
oU*oA*oC*oA*oG*dG*dT*dA*dG*dT*dT*dC*dT*dC*dA*oU*oC*oC*oU*oG,
(SEQ ID NO: 307)
oG*oU*oA*oC*oA*dG*dG*dT*dA*dG*dT*dT*dC*dT*dC*oA*oU*oC*oC*oU,
(SEQ ID NO: 308)
oA*oC*oC*oA*oG*dG*dT*dA*dC*dA*dG*dG*dT*dA*dG*oU*oU*oC*oU*oC,
(SEQ ID NO: 309)
oG*oA*oC*oC*oA*dG*dG*dT*dA*dC*dA*dG*dG*dT*dA*oG*oU*oU*oC*oU,
(SEQ ID NO: 310)
oU*oG*oA*C*oC*dA*dG*dG*dT*dA*dC*dA*dG*dG*dT*oA*xoG*oU*oU*oC,
(SEQ ID NO: 311)
oC*oC*oC*oA*oA*dA*dC*dT*dT*dG*dC*dT*dC*dA*dG*oC*oA*oG*oU*oG,
(SEQ ID NO: 312)
oU*oG*oA*oC*oA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*dA*oG*oG*oU*oA*oG,
(SEQ ID NO: 313)
oA*oU*oG*oA*oC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*oA*oG*oG*oU*oA,
(SEQ ID NO: 314)
oC*oA*oU*oG*oA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*oC*oA*oG*oG*oU,
(SEQ ID NO: 315)
oC*oC*oA*oU*oG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*oC*oC*oA*oG*oG,
(SEQ ID NO: 316)
oG*oC*oC*oA*oU*dG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*oG*oC*oC*oA*oG,
(SEQ ID NO: 246)
oG*oG*oC*oC*oA*dT*dG*dA*dC*dA*dA*dT*dC*dT*dC*oC*oG*oC*oC*oA,
(SEQ ID NO: 317)
oU*oG*oG*oC*oC*dA*dT*dG*dA*dC*dA*dA*dT*dC*dT*oC*oC*oG*oC*oC,
(SEQ ID NO: 318)
oU*oG*oU*oG*oC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*dA*oG*oC*oC*oG*oG,
(SEQ ID NO: 319)
oC*oU*oG*oU*oG*dC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*oA*oG*oC*oC*oG,
(SEQ ID NO: 320)
oC*oA*oC*oA*oG*xdC*dG*dG*dT*dC*dC*dA*dG*dC*dA*oG*oG*oA*oU*oG,
(SEQ ID NO: 321)
oU*oG*oG*oC*oC*dA*dC*dA*dG*xdC*dG*dG*dT*dC*dC*oA*oG*oC*oA*oG,
(SEQ ID NO: 322)
oA*oG*oC*oG*oC*dC*dC*dA*dC*dC*dA*dG*dT*dC*dA*oC*oA*oC*oU*oC,
(SEQ ID NO: 323)
oC*oA*oG*oC*oG*dC*dC*dC*dA*dC*dC*dA*dG*dT*dC*oA*oC*oA*oC*oU,
(SEQ ID NO: 254)
oC*oC*oA*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*dG*dT*oC*oA*oC*oA*oC,
(SEQ ID NO: 255)
oG*oC*oG*oA*oA*dT*dA*dC*dA*dC*dC*dC*dA*dG*xdC*oG*oC*oC*oC*oA,
(SEQ ID NO: 256)
oG*oG*oC*oG*oA*dA*dT*dA*dC*dA*dC*dC*dC*dA*dG*oC*oG*oC*oC*oC,
(SEQ ID NO: 324)
oU*oU*oG*oU*oA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*dC*oU*oU*oG*oC*oC,
(SEQ ID NO: 325)
oC*oU*oU*oG*oU*dA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*oC*oU*oU*oG*oC,
(SEQ ID NO: 326)
oC*oC*oU*oU*oG*dT*dA*dG*dT*dG*dG*dA*xdC*dG*dA*oU*oC*oU*oU*oG,
(SEQ ID NO: 327)
oC*oG*oG*oA*oG*dA*dC*dC*dA*dT*dC*dC*dC*dA*dG*oU*oC*oG*oA*oG,
(SEQ ID NO: 328)
oG*oA*oA*oU*oG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*dG*oU*oC*oU*oC*oC,
(SEQ ID NO: 329)
*oG*oA*oA*oU*dG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*oG*oU*oC*oU*oC,
(SEQ ID NO: 330)
oG*oG*oG*oC*oC*dT*dG*dG*dG*dA*dC*dC*dT*dC*dA*oC*oU*oG*oU*oC,
(SEQ ID NO: 331)
oU*oG*oC*oA*oC*dG*dT*dG*dT*dG*dG*dC*dT*dC*dA*oA*oG*oC*oA*oG,
(SEQ ID NO: 332)
oC*oC*oA*oC*oU*dT*dC*dA*dG*dC*dT*dG*dT*dT*dT*oC*oA*oU*oC*oC,
(SEQ ID NO: 333)
oG*oC*oG*oU*oC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*dT*oC*oA*oG*oC*oC,
(SEQ ID NO: 334)
oA*oG*oC*oG*oU*dC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*oU*oC*oA*oG*oC,
(SEQ ID NO: 335)
oC*oG*oU*oA*oG*dT*dT*dG*dA*dC*dT*dG*dG*xdC*dG*oA*oA*oG*oU*oU,
(SEQ ID NO: 336)
oG*oG*oG*oC*C*xdC*dG*dG*dA*dT*dC*dA*dC*dA*dG*oG*oA*oC*oU*oG,
(SEQ ID NO: 337)
-oU*oU*oG*oC*oC*dC*dA*dT*dC*dC*dA*xdC*dG*dT*dC*oA*oG*oG*oG*oC,
(SEQ ID NO: 338)
oG*oG*oA*oC*oG*dG*dC*dC*xdC*dG*dG*dC*dT*dT*dG*oC*oU*oG*oC*oC,
(SEQ ID NO: 339)
oU*oG*oG*oA*oA*dC*dA*xdC*dG*dG*dA*xdC*dG*dG*dC*oC*oC*oG*oG*oC,
(SEQ ID NO: 340)
oC*oA*oU*oC*oC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*dA*oU*oU*oG*oG*oG,
and
(SEQ ID NO: 341)
oG*oC*oA*oU*oC*dC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*oA*oU*oU*oG*oG,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “oC” is 5-methyl-2′-MOE-cytidine; “oU” is 5-methyl-2′-MOE-uridine; “xoG” is 7-methyl-2′-MOE-guanosine; and “*” indicates a phosphorothioate (PS) internucleoside linkage.
24 . The oligonucleotide of claim 23 , wherein the oligonucleotide is conjugated to an amine group at its 5′-end and comprises a structure selected from:
(SEQ ID NO: 302)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oG*oG*dC*dA*dT*dA*dC*dA*dC*dC*dT*dG*oG*oC*oC*oC*oG,
(SEQ ID NO: 303)
NH 2 -(CH 2 ) 6 -oC*oA*oC*oC*oA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*dT*oC*oU*oC*C*oU,
(SEQ ID NO: 304)
NH 2 -(CH 2 ) 6 -oU*oC*oA*oC*oC*dA*dA*dC*dA*xdC*dG*dT*dC*dC*dC*oU*oC*oU*oC*oC,
(SEQ ID NO: 305)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oU*oU*dC*dA*dC*dC*dA*dA*dC*dA*xdC*dG*oU*oC*C*oC*oU,
(SEQ ID NO: 306)
NH 2 -(CH 2 ) 6 -oU*oA*oC*oA*oG*dG*dT*dA*dG*dT*dT*dC*dT*dC*dA*oU*oC*oC*oU*oG,
(SEQ ID NO: 307)
NH 2 -(CH 2 ) 6 -oG*oU*oA*oC*oA*dG*dG*dT*dA*dG*dT*dT*dC*dT*dC*oA*oU*oC*oC*oU,
(SEQ ID NO: 308)
NH 2 -(CH 2 ) 6 -oA*oC*oC*oA*oG*dG*dT*dA*dC*dA*dG*dG*dT*dA*dG*oU*oU*oC*oU*oC,
(SEQ ID NO: 309)
NH 2 -(CH 2 ) 6 -oG*oA*oC*oC*oA*dG*dG*dT*dA*dC*dA*dG*dG*dT*dA*oG*oU*oU*oC*oU,
(SEQ ID NO: 310)
NH 2 -(CH 2 ) 6 -oU*oG*oA*C*oC*dA*dG*dG*dT*dA*dC*dA*dG*dG*dT*oA*xoG*oU*oU*oC,
(SEQ ID NO: 311)
NH 2 -(CH 2 ) 6 -oC*oC*oC*oA*oA*dA*dC*dT*dT*dG*dC*dT*dC*dA*dG*oC*oA*oG*oU*oG,
(SEQ ID NO: 312)
NH 2 -(CH 2 ) 6 -oU*oG*oA*oC*oA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*dA*oG*oG*oU*oA*oG,
(SEQ ID NO: 313)
NH 2 -(CH 2 ) 6 -oA*oU*oG*oA*oC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*dC*oA*oG*oG*oU*oA,
(SEQ ID NO: 314)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oG*oA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*dC*oC*oA*oG*oG*oU,
(SEQ ID NO: 315)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oU*oG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*dG*oC*oC*oA*oG*oG,
(SEQ ID NO: 316)
NH 2 -(CH 2 ) 6 -oG*oC*oC*oA*oU*dG*dA*dC*dA*dA*dT*dC*dT*dC*xdC*oG*oC*oC*oA*oG,
(SEQ ID NO: 246)
NH 2 -(CH 2 ) 6 -oG*oG*oC*oC*oA*dT*dG*dA*dC*dA*dA*dT*dC*dT*dC*oC*oG*oC*oC*oA,
(SEQ ID NO: 317)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oC*oC*dA*dT*dG*dA*dC*dA*dA*dT*dC*dT*oC*oC*oG*oC*oC,
(SEQ ID NO: 318)
NH 2 -(CH 2 ) 6 -oU*oG*oU*oG*oC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*dA*oG*oC*oC*oG*oG,
(SEQ ID NO: 319)
NH 2 -(CH 2 ) 6 -oC*oU*oG*oU*oG*dC*dA*xdC*dG*dT*dA*dG*dC*dC*dA*oA*oG*oC*oC*oG,
(SEQ ID NO: 320)
NH 2 -(CH 2 ) 6 -oC*oA*oC*oA*oG*xdC*dG*dG*dT*dC*dC*dA*dG*dC*dA*oG*oG*oA*oU*oG,
(SEQ ID NO: 321)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oC*oC*dA*dC*dA*dG*xdC*dG*dG*dT*dC*dC*oA*oG*oC*oA*oG,
(SEQ ID NO: 322)
NH 2 -(CH 2 ) 6 -oA*oG*oC*oG*oC*dC*dC*dA*dC*dC*dA*dG*dT*dC*dA*oC*oA*oC*oU*oC,
(SEQ ID NO: 323)
NH 2 -(CH 2 ) 6 -oC*oA*oG*oC*oG*dC*dC*dC*dA*dC*dC*dA*dG*dT*dC*oA*oC*oA*oC*oU,
(SEQ ID NO: 254)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oG*oC*dG*dC*dC*dC*dA*dC*dC*dA*dG*dT*oC*oA*oC*oA*oC,
(SEQ ID NO: 255)
NH 2 -(CH 2 ) 6 -oG*oC*oG*oA*oA*dT*dA*dC*dA*dC*dC*dC*dA*dG*xdC*oG*oC*oC*oC*oA,
(SEQ ID NO: 256)
NH 2 -(CH 2 ) 6 -oG*oG*oC*oG*oA*dA*dT*dA*dC*dA*dC*dC*dC*dA*dG*oC*oG*oC*oC*oC,
(SEQ ID NO: 324)
NH 2 -(CH 2 ) 6 -oU*oU*oG*oU*oA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*dC*oU*oU*oG*oC*oC,
(SEQ ID NO: 325)
NH 2 -(CH 2 ) 6 -oC*oU*oU*oG*oU*dA*dG*dT*dG*dG*dA*xdC*dG*dA*dT*oC*oU*oU*oG*oC,
(SEQ ID NO: 326)
NH 2 -(CH 2 ) 6 -oC*oC*oU*oU*oG*dT*dA*dG*dT*dG*dG*dA*xdC*dG*dA*oU*oC*oU*oU*oG,
(SEQ ID NO: 327)
NH 2 -(CH 2 ) 6 -oC*oG*oG*oA*oG*dA*dC*dC*dA*dT*dC*dC*dC*dA*dG*oU*oC*oG*oA*oG,
(SEQ ID NO: 328)
NH 2 -(CH 2 ) 6 -oG*oA*oA*oU*oG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*dG*oU*oC*oU*oC*oC,
(SEQ ID NO: 329)
NH 2 -(CH 2 ) 6 -oC*oG*oA*oA*oU*dG*dT*dC*xdC*dG*dA*dC*dA*dG*dT*oG*oU*oC*oU*oC,
(SEQ ID NO: 330)
NH 2 -(CH 2 ) 6 -oG*oG*oG*oC*oC*dT*dG*dG*dG*dA*dC*dC*dT*dC*dA*oC*oU*oG*oU*oC,
(SEQ ID NO: 331)
NH 2 -(CH 2 ) 6 -oU*oG*oC*oA*oC*dG*dT*dG*dT*dG*dG*dC*dT*dC*dA*oA*oG*oC*oA*oG,
(SEQ ID NO: 332)
NH 2 -(CH 2 ) 6 -oC*oC*oA*oC*oU*dT*dC*dA*dG*dC*dT*dG*dT*dT*dT*oC*oA*oU*oC*oC,
(SEQ ID NO: 333)
NH 2 -(CH 2 ) 6 -oG*oC*oG*oU*oC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*dT*oC*oA*oG*oC*oC,
(SEQ ID NO: 334)
NH 2 -(CH 2 ) 6 -oA*oG*oC*oG*oU*dC*dA*dC*dC*dT*xdC*dG*dG*dC*dC*oU*oC*oA*oG*oC,
(SEQ ID NO: 335)
NH 2 -(CH 2 ) 6 -oC*oG*oU*oA*oG*dT*dT*dG*dA*dC*dT*dG*dG*xdC*dG*oA*oA*oG*oU*oU,
(SEQ ID NO: 336)
NH 2 -(CH 2 ) 6 -oG*oG*oG*oC*C*xdC*dG*dG*dA*dT*dC*dA*dC*dA*dG*oG*oA*oC*oU*oG,
(SEQ ID NO: 337)
NH 2 -(CH 2 ) 6 -oU*oU*oG*oC*oC*dC*dA*dT*dC*dC*dA*xdC*dG*dT*dC*oA*oG*oG*oG*oC,
(SEQ ID NO: 338)
NH 2 -(CH 2 ) 6 -oG*oG*oA*oC*oG*dG*dC*dC*xdC*dG*dG*dC*dT*dT*dG*oC*oU*oG*oC*oC,
(SEQ ID NO: 339)
NH 2 -(CH 2 ) 6 -oU*oG*oG*oA*oA*dC*dA*xdC*dG*dG*dA*xdC*dG*dG*dC*oC*oC*oG*oG*oC,
(SEQ ID NO: 340)
NH 2 -(CH 2 ) 6 -oC*oA*oU*oC*oC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*dA*oU*oU*oG*oG*oG,
and
(SEQ ID NO: 341)
NH 2 -(CH 2 ) 6 -oG*oC*oA*oU*oC*dC*dA*dA*dA*dA*xdC*dG*dT*dG*dG*oA*oU*oU*oG*oG,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “oC” is 5-methyl-2′-MOE-cytidine; “oU” is 5-methyl-2′-MOE-uridine; “xoG” is 7-methyl-2′-MOE-guanosine; and “*” indicates a phosphorothioate (PS) internucleoside linkage,
and optionally wherein a phosphodiester linkage or other moiety is present between the 5′-NH 2 —(CH 2 ) 6 — and the oligonucleotide.
25 . An oligonucleotide comprising a structure selected from:
(SEQ ID NO: 276)
+G*x+C*oA*xoC*dG*dT*dG*dT*dG*dG*xdC*dT*xoC*oA*+A*+G,
(SEQ ID NO: 348)
+A*x+C*xoC*oA*dA*xdC*dA*xdC*dG*dT*xdC*xdC*xoC*oU*x+C*+U,
(SEQ ID NO: 354)
x+C*x+C*xoC*oG*dG*dA*dT*xdC*dA*xdC*dA*dG*oG*oA*x+C*+U,
(SEQ ID NO: 350)
+G*+U*oA*oG*dT*dT*dG*dA*xdC*dT*dG*dG*xoC*oG*+A*+A,
(SEQ ID NO: 345)
x+C*+A*oU*oG*dA*xdC*dA*dA*dT*xdC*dT*xdC*xoC*oG*x+C*x+C,
(SEQ ID NO: 286)
xoC*xoC*+A*+A*dA*xdC*dT*dT*dG*xdC*dT*xdC*+A*+G*xoC*oA,
(SEQ ID NO: 352)
xoC*oU*+U*x+C*dA*dG*xdC*dT*dG*dT*dT*dT*x+C*+A*oU*xoC,
(SEQ ID NO: 357)
x+C*+G*oU*xoC*dA*xdC*xdC*dT*xdC*dG*dG*xdC*xoC*oU*x+C*+A,
(SEQ ID NO: 275)
x+C*+A*xoC*oG*dT*dG*dT*dG*dG*xdC*dT*xdC*oA*oA*+G*x+C,
(SEQ ID NO: 275)
xoC*oA*x+C*+G*dT*dG*dT*dG*dG*xdC*dT*xdC*+A*+A*oG*xoC,
(SEQ ID NO: 276)
oG*xoC*+A*x+C*dG*dT*dG*dT*dG*dG*xdC*dT*x+C*+A*oA*oG,
(SEQ ID NO: 342)
+A*x+C*oG*oU*dG*dT*dG*dG*xdC*dT*xdC*dA*oA*oG*x+C*+A,
(SEQ ID NO: 342)
oA*xoC*+G*+U*dG*dT*dG*dG*xdC*dT*xdC*dA*+A*+G*xoC*oA,
(SEQ ID NO: 278)
x+C*+A*oA*oA*xdC*dT*dT*dG*xdC*dT*xdC*dA*oG*xoC*+A*+G,
(SEQ ID NO: 343)
+A*x+C*oU*oU*xdC*dA*dG*xdC*dT*dG*dT*dT*oU*xoC*+A*+U,
(SEQ ID NO: 344)
+U*+A*oG*oU*dT*dG*dA*xdC*dT*dG*dG*xdC*oG*A*+A*+G,
(SEQ ID NO: 281)
+G*x+C*xoC*xoC*dG*dG*dA*dT*dC*dA*xdC*dA*oG*oG*+A*x+C,
(SEQ ID NO: 346)
+G*+U*xoC*oA*xdC*xdC*dT*xdC*dG*dG*xdC*dC*oU*xoC*+A*+G,
(SEQ ID NO: 347)
x+C*x+C*A*oG*dG*dT*dA*xdC*dA*dG*dG*dT*oA*oG*+U*+U,
(SEQ ID NO: 286)
x+C*x+C*oA*oA*dA*xdC*dT*dT*dG*xdC*dT*xdC*oA*oG*x+C*+A,
(SEQ ID NO: 349)
x+C*+A*xoC*oU*dT*xdC*dA*dG*xdC*dT*dG*dT*oU*oU*x+C*+A,
(SEQ ID NO: 289)
+G*+G*xoC*xoC*xdC*dG*dG*dA*dT*xdC*dA*xdC*oA*oG*+G*+A,
(SEQ ID NO: 351)
+A*+A*oA*xoC*dT*dT*dG*xdC*dT*xdC*dA*dG*xoC*oA*+G*+U,
(SEQ ID NO: 352)
x+C*+U*oU*xoC*dA*dG*xdC*dT*dG*dT*dT*dT*xoC*oA*+U*x+C,
(SEQ ID NO: 353)
+A*+G*oU*oU*dG*dA*xdC*dT*dG*dG*xdC*dG*oA*oA*+G*+U,
(SEQ ID NO: 278)
XoC*oA*+A*+A*xdC*dT*dT*dG*xdC*dT*xdC*dA*+G*x+C*oA*oG,
(SEQ ID NO: 343)
oA*xoC*+U*+U*xdC*dA*dG*xdC*dT*dG*dT*dT*+U*x+C*oA*oU,
(SEQ ID NO: 344)
oU*oA*+G*+U*dT*dG*dA*xdC*dT*dG*dG*xdC*+G*+A*oA*oG,
(SEQ ID NO: 281)
oG*xoC*x+C*x+C*dG*dG*dA*dT*dC*dA*dC*dA*+G*+G*oA*xoC,
(SEQ ID NO: 349)
xoC*oA*x+C*+U*dT*xdC*dA*dG*xdC*dT*dG*dT*+U*+U*xoC*oA,
(SEQ ID NO: 350)
oG*oU*+A*+G*dT*dT*dG*dA*xdC*dT*dG*dG*x+C*+G*oA*oA,
(SEQ ID NO: 289)
oG*oG*x+C*x+C*xdC*G*dG*dA*dT*xdC*dA*xdC*+A*+G*oG*oA,
(SEQ ID NO: 351)
oA*oA*+A*x+C*dT*dT*dG*xdC*dT*xdC*dA*dG*x+C*+A*oG*oU,
(SEQ ID NO: 353)
oA*oG*+U*+U*dG*dA*xdC*dT*dG*dG*xdC*dG*+A*+A*oG*oU,
(SEQ ID NO: 354)
xoC*xoC*x+C*+G*dG*dA*dT*xdC*dA*xdC*dA*dG*+G*+A*xoC*oU,
(SEQ ID NO: 355)
x+C*x+C*A*oU*dG*dA*xdC*dA*dA*dT*xdC*dT*xoC*xoC*+G*x+C,
(SEQ ID NO: 356)
+A*+U*G*oA*xdC*dA*dA*dT*xdC*dT*xdC*xdC*oG*xoC*x+C*+A,
(SEQ ID NO: 358)
+U*x+C*oA*xoC*xdC*dT*xdC*dG*dG*xdC*xdC*dT*xoC*oA*+G*x+C,
(SEQ ID NO: 359)
+A*x+C*xoC*oA*dG*dG*dT*dA*xdC*dA*dG*dG*oU*oA*+G*+U,
(SEQ ID NO: 360)
x+C*+A*oG*oG*dT*dA*xdC*dA*dG*dG*dT*dA*oG*oU*+U*x+C,
(SEQ ID NO: 361)
x+C*+A*xoC*xoC*dA*dA*xdC*dA*xdC*dG*dT*xdC*xoC*xoC*+U*x+C,
and
(SEQ ID NO: 362)
x+C*x+C*oA*oA*xdC*dA*xdC*dG*dT*xdC*xdC*xdC*oU*xoC*+U*x+C,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “xoC” is 5-methyl-2′-MOE-cytidine; “x+C” is 5-methyl LNA cytidine; “+N” is an LNA nucleoside; “oU” is 5-methyl-2′-MOE-uridine; “+U” is 5-methyl LNA uridine; “*” indicates a phosphorothioate (PS) internucleoside linkage.
26 . The oligonucleotide of claim 25 , wherein the oligonucleotide is conjugated to an amine group at its 5′-end and comprises a structure selected from:
(SEQ ID NO: 276)
NH 2 -(CH 2 ) 6 -+G*x+C*oA*xoC*dG*dT*dG*dT*dG*dG*xdC*dT*xoC*oA*+A*+G,
(SEQ ID NO: 348)
NH 2 -(CH 2 ) 6 -+A*x+C*xoC*oA*dA*xdC*dA*xdC*dG*dT*xdC*xdC*xoC*oU*x+C*+U,
(SEQ ID NO: 354)
NH 2 -(CH 2 ) 6 -x+C*x+C*xoC*oG*dG*dA*dT*xdC*dA*xdC*dA*dG*oG*oA*x+C*+U,
(SEQ ID NO: 350)
NH 2 -(CH 2 ) 6 -+G*+U*oA*oG*dT*dT*dG*dA*xdC*dT*dG*dG*xoC*oG*+A*+A,
(SEQ ID NO: 345)
NH 2 -(CH 2 ) 6 -x+C*+A*oU*oG*dA*xdC*dA*dA*dT*xdC*dT*xdC*xoC*oG*x+C*x+C,
(SEQ ID NO: 286)
NH 2 -(CH 2 ) 6 -xoC*xoC*+A*+A*dA*xdC*dT*dT*dG*xdC*dT*xdC*+A*+G*xoC*oA,
(SEQ ID NO: 352)
NH 2 -(CH 2 ) 6 -xoC*oU*+U*x+C*dA*dG*xdC*dT*dG*dT*dT*dT*x+C*+A*oU*xoC,
(SEQ ID NO: 357)
NH 2 -(CH 2 ) 6 -x+C*+G*oU*xoC*dA*xdC*xdC*dT*xdC*dG*dG*xdC*xoC*oU*x+C*+A,
(SEQ ID NO: 275)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*oG*dT*dG*dT*dG*dG*xdC*dT*xdC*oA*oA*+G*x+C,
(SEQ ID NO: 275)
NH 2 -(CH 2 ) 6 -xoC*oA*x+C*+G*dT*dG*dT*dG*dG*xdC*dT*xdC*+A*+A*oG*xoC,
(SEQ ID NO: 276)
NH 2 -(CH 2 ) 6 -oG*xoC*+A*x+C*dG*dT*dG*dT*dG*dG*xdC*dT*x+C*+A*oA*oG,
(SEQ ID NO: 342)
NH 2 -(CH 2 ) 6 -+A*x+C*oG*oU*dG*dT*dG*dG*xdC*dT*xdC*dA*oA*oG*x+C*+A,
(SEQ ID NO: 342)
NH 2 -(CH 2 ) 6 -oA*xoC*+G*+U*dG*dT*dG*dG*xdC*dT*xdC*dA*+A*+G*xoC*oA,
(SEQ ID NO: 278)
NH 2 -(CH 2 ) 6 -x+C*+A*oA*oA*xdC*dT*dT*dG*xdC*dT*xdC*dA*oG*xoC*+A*+G,
(SEQ ID NO: 343)
NH 2 -(CH 2 ) 6 -+A*x+C*oU*oU*xdC*dA*dG*xdC*dT*dG*dT*dT*oU*xoC*+A*+U,
(SEQ ID NO: 344)
NH 2 -(CH 2 ) 6 -+U*+A*oG*oU*dT*dG*dA*xdC*dT*dG*dG*xdC*oG*A*+A*+G,
(SEQ ID NO: 281)
NH 2 -(CH 2 ) 6 -+G*x+C*xoC*xoC*dG*dG*dA*dT*dC*dA*xdC*dA*oG*oG*+A*x+C,
(SEQ ID NO: 346)
NH 2 -(CH 2 ) 6 -+G*+U*xoC*oA*xdC*xdC*dT*xdC*dG*dG*xdC*dC*oU*xoC*+A*+G,
(SEQ ID NO: 347)
NH 2 -(CH 2 ) 6 -x+C*x+C*A*oG*dG*dT*dA*xdC*dA*dG*dG*dT*oA*oG*+U*+U,
(SEQ ID NO: 286)
NH 2 -(CH 2 ) 6 -x+C*x+C*oA*oA*dA*xdC*dT*dT*dG*xdC*dT*xdC*oA*oG*x+C*+A,
(SEQ ID NO: 349)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*oU*dT*xdC*dA*dG*xdC*dT*dG*dT*oU*oU*x+C*+A,
(SEQ ID NO: 289)
NH 2 -(CH 2 ) 6 -+G*+G*xoC*xoC*xdC*dG*dG*dA*dT*xdC*dA*xdC*oA*oG*+G*+A,
(SEQ ID NO: 351)
NH 2 -(CH 2 ) 6 -+A*+A*oA*xoC*dT*dT*dG*xdC*dT*xdC*dA*dG*xoC*oA*+G*+U,
(SEQ ID NO: 352)
NH 2 -(CH 2 ) 6 -x+C*+U*oU*xoC*dA*dG*xdC*dT*dG*dT*dT*dT*xoC*oA*+U*x+C,
(SEQ ID NO: 353)
NH 2 -(CH 2 ) 6 -+A*+G*oU*oU*dG*dA*xdC*dT*dG*dG*xdC*dG*oA*oA*+G*+U,
(SEQ ID NO: 278)
NH 2 -(CH 2 ) 6 -XoC*oA*+A*+A*xdC*dT*dT*dG*xdC*dT*xdC*dA*+G*x+C*oA*oG,
(SEQ ID NO: 343)
NH 2 -(CH 2 ) 6 -oA*xoC*+U*+U*xdC*dA*dG*xdC*dT*dG*dT*dT*+U*x+C*oA*oU,
(SEQ ID NO: 344)
NH 2 -(CH 2 ) 6 -oU*oA*+G*+U*dT*dG*dA*xdC*dT*dG*dG*xdC*+G*+A*oA*oG,
(SEQ ID NO: 281)
NH 2 -(CH 2 ) 6 -oG*xoC*x+C*x+C*dG*dG*dA*dT*dC*dA*dC*dA*+G*+G*oA*xoC,
(SEQ ID NO: 349)
NH 2 -(CH 2 ) 6 -xoC*oA*x+C*+U*dT*xdC*dA*dG*xdC*dT*dG*dT*+U*+U*xoC*oA,
(SEQ ID NO: 350)
NH 2 -(CH 2 ) 6 -oG*oU*+A*+G*dT*dT*dG*dA*xdC*dT*dG*dG*x+C*+G*oA*oA,
(SEQ ID NO: 289)
NH 2 -(CH 2 ) 6 -oG*oG*x+C*x+C*xdC*G*dG*dA*dT*xdC*dA*xdC*+A*+G*oG*oA,
(SEQ ID NO: 351)
NH 2 -(CH 2 ) 6 -oA*oA*+A*x+C*dT*dT*dG*xdC*dT*xdC*dA*dG*x+C*+A*oG*oU,
(SEQ ID NO: 353)
NH 2 -(CH 2 ) 6 -oA*oG*+U*+U*dG*dA*xdC*dT*dG*dG*xdC*dG*+A*+A*oG*oU,
(SEQ ID NO: 354)
NH 2 -(CH 2 ) 6 -xoC*xoC*x+C*+G*dG*dA*dT*xdC*dA*xdC*dA*dG*+G*+A*xoC*oU,
(SEQ ID NO: 355)
NH 2 -(CH 2 ) 6 -x+C*x+C*A*oU*dG*dA*xdC*dA*dA*dT*xdC*dT*xoC*xoC*+G*x+C,
(SEQ ID NO: 356)
NH 2 -(CH 2 ) 6 -+A*+U*G*oA*xdC*dA*dA*dT*xdC*dT*xdC*xdC*oG*xoC*x+C*+A,
(SEQ ID NO: 358)
NH 2 -(CH 2 ) 6 -+U*x+C*oA*xoC*xdC*dT*xdC*dG*dG*xdC*xdC*dT*xoC*oA*+G*x+C,
(SEQ ID NO: 359)
NH 2 -(CH 2 ) 6 -+A*x+C*xoC*oA*dG*dG*dT*dA*xdC*dA*dG*dG*oU*oA*+G*+U,
(SEQ ID NO: 360)
NH 2 -(CH 2 ) 6 -x+C*+A*oG*oG*dT*dA*xdC*dA*dG*dG*dT*dA*oG*oU*+U*x+C,
(SEQ ID NO: 361)
NH 2 -(CH 2 ) 6 -x+C*+A*xoC*xoC*dA*dA*xdC*dA*xdC*dG*dT*xdC*xoC*xoC*+U*x+C,
and
(SEQ ID NO: 362)
NH 2 -(CH 2 ) 6 -x+C*x+C*oA*oA*xdC*dA*xdC*dG*dT*xdC*xdC*xdC*oU*xoC*+U*x+C,
wherein “xdC” is 5-methyl-deoxycytidine; “dN” is 2′-deoxyribonucleoside; “oN” is 2′-MOE modified ribonucleoside; “xoC” is 5-methyl-2′-MOE-cytidine; “x+C” is 5-methyl LNA cytidine; “+N” is an LNA nucleoside; “oU” is 5-methyl-2′-MOE-uridine; “+U” is 5-methyl LNA uridine; “*” indicates a phosphorothioate (PS) internucleoside linkage,
and optionally wherein a phosphodiester linkage or other moiety is present between the 5′-NH 2 —(CH 2 ) 6 — and the oligonucleotide.
27 . A composition comprising the oligonucleotide of claim 23 in sodium salt form.