초록

The present invention provides compounds and methods for modulating expression of a protein, including, but not limited to, modulating splicing of a pre-mRNA to modulate the amount of one or more variants of a protein.

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1. An oligomeric compound comprising a contiguous sequence of nucleosides having the formula I: T1-(Nu1)n1-(Nu2)n2-(Nu3)n3-(Nu4)n4-(Nu5)n5-T2, wherein:Nu1 and Nu5 are, independently, 2′ stabilizing nucleosides;Nu2 and Nu4 are β-D-2′-deoxy-2′-fluororibofuranosyl nucleosides;Nu3 is a 2′-modified nucle

1. An oligomeric compound comprising a contiguous sequence of nucleosides having the formula I: T1-(Nu1)n1-(Nu2)n2-(Nu3)n3-(Nu4)n4-(Nu5)n5-T2, wherein:Nu1 and Nu5 are, independently, 2′ stabilizing nucleosides;Nu2 and Nu4 are β-D-2′-deoxy-2′-fluororibofuranosyl nucleosides;Nu3 is a 2′-modified nucleoside;each of n1 and n5 is, independently, from 0 to 3;the sum of n2 plus n4 is between 10 and 25;n3 is from 0 and 5; andeach T1 and T2 is, independently, H, a hydroxyl protecting group, an optionally linked conjugate group or a capping group, wherein the sequence is complementary to a portion of a pre-mRNA encoding Bcl-x, MyD88, Lamin A, SMN2, or a TNF receptor. 2. The oligomeric compound of claim 1, wherein: the sum of n2 and n4 is 16 or 17;n1 is 2;n3 is 2 or 3; andn5 is 2. 3. The oligomeric compound of claim 1, wherein the formula I is selected from: a) formula I: n1=2, n2=19, n3=0, n4=0, n5=2;b) formula I: n1=2, n2=2, n3=3, n4=14, n5=2;c) formula I: n1=2, n2=5, n3=3, n4=11, n5=2;d) formula I: n1=2, n2=8, n3=3, n4=8, n5=2;e) formula I: n1=2, n2=11, n3=3, n4=5, n5=2;f) formula I: n1=2, n2=14, n3=3, n4=2, n5=2;g) formula I: n1=2, n2=9, n3=3, n4=7, n5=2;h) formula I: n1=2, n2=10, n3=3, n4=6, n5=2;i) formula I: n1=2, n2=12, n3=3, n4=4, n5=2;j) formula I: n1=2, n2=3, n3=3, n4=13, n5=2;k) formula I: n1=2, n2=4, n3=3, n4=12, n5=2;l) formula I: n1=2, n2=6, n3=3, n4=10, n5=2;m) formula I: n1=2, n2=7, n3=3, n4=9, n5=2;n) formula I: n1=2, n2=13, n3=3, n4=3, n5=2;o) formula I: n1=2, n2=8, n3=6, n4=5, n5=2;p) formula I: n1=2, n2=2, n3=2, n4=15, n5=2;q) formula I: n1=2, n2=3, n3=2, n4=14, n5=2;r) formula I: n1=2, n2=4, n3=2, n4=13, n5=2;s) formula: n1=2, n2=5, n3=2, n4=12, n5=2;t) formula I: n1=2, n2=6, n3=2, n4=11, n5=2;u) formula I: n1=2, n2=7, n3=2, n4=10, n5=2;v) formula I: n1=2, n2=8, n3=2, n4=9, n5=2;w) formula I: n1=2, n2=9, n3=2, n4=8, n5=2;x) formula I: n1=2, n2=10, n3=2, n4=7, n5=2;y) formula I: n1=2, n2=11, n3=2, n4=6, n5=2;z) formula I: n1=2, n2=12, n3=2, n4=5, n5=2;aa) formula I: n1=2, n2=13, n3=2, n4=4, n5=2;bb) formula I: n5=2, n2=14, n3=2, n4=3, n5=2;cc) formula I: n1=2, n2=15, n3=2, n4=2, n5=2; anddd) formula I: n1=2, n2=9, n3=3, n4=4, n5=2. 4. The oligomeric compound of claim 3, wherein Nu1 and Nu5 are, independently, 2′-modified nucleosides. 5. The oligomeric compound of claim 4 wherein each of the 2-modified nucleosides independently comprises a 2′-substituent group selected from O—C1-C12 alkyl, substituted O—C1-C12 alkyl, O—C2-C12 alkenyl, substituted O—C2-C12 alkenyl, O—C2-C12 alkynyl, substituted O—C2-C12 alkynyl, amino, substituted amino, amide, substituted amide, aralkyl, substituted aralkyl, O-aralkyl, substituted O-aralkyl, N3, SH, CN, OCN, CF3, OCF3, SOCH3, —SO2CH3, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino and polyalkylamino; and wherein each substituent group is, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, O—C1-C12 alkyl, substituted O—C1-C12 alkyl, S—C1-C12 alkyl, substituted S—C1-C12 alkyl, acyl (C(═O)—H), substituted acyl, amino, substituted amino, amide, substituted amide, C1-C12 alkylamino, substituted C1-C12 alkylamino, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkoxy, C1-C12 alkylaminooxy, substituted C1-C12 alkylaminooxy, guanidinyl, substituted guanidinyl or a protecting group. 6. The oligomeric compound of claim 5 wherein each 2′-substituent group is independently selected from O—C1-C12 alkyl, O—CH2—CH2—CH2—NH2, O—(CH2)2—O—N(R6)2, O—CH2C(═O)—N(R6)2, O—(CH2)2—O—(CH2)2—N(R6)2, O—CH2—CH2—CH2—NHR6, N3, O—CH2—CH═CH2, NHCOR6 or O—CH2—N(H)—C(═NR6)[N(R6)2]; wherein each R6 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl or a protecting group wherein the substituent groups are halogen, hydroxyl, amino, azido, cyano, haloalkyl, alkenyl, alkoxy, thioalkoxy, haloalkoxy or aryl. 7. The oligomeric compound of claim 5 wherein each 2′-substituent group is, independently, O(CH2)0-2CH3, O(CH2)2OCH3, O(CH2)2SCH3, OCH2C(H)CH2, O(CH2)2ON(CH3)2 or OCH2C(═O)N(H)CH3. 8. The oligomeric compound of claim 7 wherein each 2′-substituent group is, independently, OCH3 or O—(CH2)2—OCH3. 9. The oligomeric compound of claim 8 wherein each 2′-substituent group is O—(CH2)2—OCH3. 10. The oligomeric compound of claim 4, wherein the 2′-modified nucleoside is a bicyclic sugar modified nucleoside. 11. The oligomeric compound of claim 10, wherein each bicyclic sugar modified nucleoside independently comprises a D or L sugar in the alpha or beta configuration. 12. The oligomeric compound of claim 10 wherein each of the bicyclic sugar modified nucleosides independently comprises a bridge group between the 2′ and the 4′-carbon atoms comprising from 1 to 8 linked biradical groups independently selected from —O—, —S—, —N(R1)—, —C(R1)(R2)—, —C(R1)═C(R1)—, —C(R1)═N—, —C(═NR1)—, —Si(R1)(R2)—, —S(═O)2—, —S(═O)—, —C(═O)— and —C(═S)—; each R1 and R2 is, independently, H, hydroxyl, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, a heterocycle radical, a substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, substituted oxy (—O—), amino, substituted amino, azido, carboxyl, substituted carboxyl, acyl, substituted acyl, CN, thiol, substituted thiol, sulfonyl (S(═O)2—H), substituted sulfonyl, sulfoxyl (S(═O)—H) or substituted sulfoxyl; andwherein each substituent group is, independently, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, amino, substituted amino, acyl, substituted acyl, C1-C12 aminoalkyl, C1-C12 aminoalkoxy, substituted C1-C12 aminoalkyl, substituted C1-C12 aminoalkoxy or a protecting group. 13. The oligomeric compound of claim 10 wherein each bicyclic sugar modified nucleoside independently comprises from 1 to 4 of the linked biradical groups. 14. The oligomeric compound of claim 10 wherein each bicyclic sugar modified nucleoside independently comprises 2 or 3 of the linked biradical groups. 15. The oligomeric compound of claim 10 wherein each bicyclic sugar modified nucleoside comprises 2 of the linked biradical groups. 16. The oligomeric compound of claim 12 wherein each bridge group is, independently, —CH2—, —(CH2)2—, —CH2—O—, —(CH2)2—O— or —CH2—N(R3)—O— wherein R3 is H or C1-C12 alkyl. 17. The oligomeric compound of claim 12 wherein each bridge group is, independently, —CH2—O— or —(CH2)2—O—. 18. The oligomeric compound of claim 2, wherein Nu1 is O—(CH2)2—OCH3, Nu3 is O—(CH2)2—OCH3, Nu5O—(CH2)2—OCH3, T1 is H and T2 is H, and wherein formula I is selected from: a. formula I: n1=2, n2=19, n3=0, n4=0, n5=2;b. formula I: n1=2, n2=2, n3=3, n4=14, n5=2;c. formula I: n1=2, n2=5, n3=3, n4=11, n5=2;d. formula I: n1=2, n2=8, n3=3, n4=8, n5=2;e. formula I: n1=2, n2=11, n3=3, n4=5, n5=2;f. formula I: n1=2, n2=14, n3=3, n4=2, n5=2;g. formula I: n1=2, n2=9, n3=3, n4=7, n5=2;h. formula I: n1=2, n2=10, n3=3, n4=6, n5=2;i. formula I: n1=2, n2=12, n3=3, n4=4, n5=2;j. formula I: n1=2, n2=3, n3=3, n4=13, n5=2;k. formula I: n1=2, n2=4, n3=3, n4=12, n5=2;l. formula I: n1=2, n2=6, n3=3, n4=10, n5=2;m. formula I: n1=2, n2=7, n3=3, n4=9, n5=2;n. formula I: n1=2, n2=13, n3=3, n4=3, n5=2;o. formula I: n1=2, n2=8, n3=6, n4=5, n5=2;p. formula I: n1=2, n2=2, n3=2, n4=15, n5=2;q. formula I: n1=2, n2=3, n3=2, n4=14, n5=2;r. formula I: n1=2, n2=4, n3=2, n4=13, n5=2;s. formula I: n1=2, n2=5, n3=2, n4=12, n5=2;t. formula I: n1=2, n2=6, n3=2, n4=11, n5=2;u. formula I: n1=2, n2=7, n3=2, n4=10, n5=2;v. formula I: n1=2, n2=8, n3=2, n4=9, n5=2;w. formula I: n1=2, n2=9, n3=2, n4=8, n5=2;x. formula I: n1=2, n2=10, n3=2, n4=7, n5=2;y. formula I: n1=2, n2=11, n3=2, n4=6, n5=2;z. formula I: n1=2, n2=12, n3=2, n4=5, n5=2;aa. formula I: n1=2, n2=13, n3=2, n4=4, n5=2;bb. formula I: n5=2, n2=14, n3=2, n4=3, n5=2;cc. formula I: n1=2, n2=15, n3=2, n4=2, n5=2; anddd. formula I: n1=2, n2=9, n3=3, n4=4, n5=2. 19. The oligomeric compound of claim 18 wherein the oligomeric compound comprises at least one phosphorothioate internucleoside linkage. 20. The oligomeric compound of claim 1 wherein each internucleoside linkage comprises a phosphorothioate internucleoside linkage.