Compounds and methods for modulating protein expression

1. An oligomeric compound comprising a contiguous sequence of nucleosides having the formula I:

T 1 -(Nu 1 ) n1 -(Nu 2 ) n2 -(Nu 3 ) n3 -(Nu 4 ) n4 -(Nu 5 ) n5 -T 2 , wherein:

Nu 1 and Nu 5 are, independently, 2′ stabilizing nucleosides;

Nu 2 and Nu 4 are β-D-2′-deoxy-2′-fluororibofuranosyl nucleosides;

Nu 3 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; and

each T 1 and T 2 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; and

n5 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; and

dd) formula I: n1=2, n2=9, n3=3, n4=4, n5=2.

4. The oligomeric compound of claim 3 , wherein Nu 1 and Nu 5 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—C 1 -C 12 alkyl, substituted O—C 1 -C 12 alkyl, O—C 2 -C 12 alkenyl, substituted O—C 2 -C 12 alkenyl, O—C 2 -C 12 alkynyl, substituted O—C 2 -C 12 alkynyl, amino, substituted amino, amide, substituted amide, aralkyl, substituted aralkyl, O-aralkyl, substituted O-aralkyl, N 3 , SH, CN, OCN, CF 3 , OCF 3 , SOCH 3 , —SO 2 CH 3 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino and polyalkylamino; and

wherein each substituent group is, independently, halogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, O—C 1 -C 12 alkyl, substituted O—C 1 -C 12 alkyl, S—C 1 -C 12 alkyl, substituted S—C 1 -C 12 alkyl, acyl (C(═O)—H), substituted acyl, amino, substituted amino, amide, substituted amide, C 1 -C 12 alkylamino, substituted C 1 -C 12 alkylamino, C 1 -C 12 aminoalkoxy, substituted C 1 -C 12 aminoalkoxy, C 1 -C 12 alkylaminooxy, substituted C 1 -C 12 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—C 1 -C 12 alkyl, O—CH 2 —CH 2 —CH 2 —NH 2 , O—(CH 2 ) 2 —O—N(R 6 )2, O—CH 2 C(═O)—N(R 6 ) 2 , O—(CH 2 ) 2 —O—(CH 2 ) 2 —N(R 6 ) 2 , O—CH 2 —CH 2 —CH 2 —NHR 6 , N 3 , O—CH 2 —CH═CH 2 , NHCOR 6 or O—CH 2 —N(H)—C(═NR 6 )[N(R 6 ) 2 ];

wherein each R 6 is, independently, H, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 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(CH 2 ) 0-2 CH 3 , O(CH 2 ) 2 OCH 3 , O(CH 2 ) 2 SCH 3 , OCH 2 C(H)CH 2 , O(CH 2 ) 2 ON(CH 3 ) 2 or OCH 2 C(═O)N(H)CH 3 .

8. The oligomeric compound of claim 7 wherein each 2′-substituent group is, independently, OCH 3 or O—(CH 2 ) 2 —OCH 3 .

9. The oligomeric compound of claim 8 wherein each 2′-substituent group is O—(CH 2 ) 2 —OCH 3 .

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(R 1 )—, —C(R 1 )(R 2 )—, —C(R 1 )═C(R 1 )—, —C(R 1 )═N—, —C(═NR 1 )—, —Si(R 1 )(R 2 )—, —S(═O) 2 —, —S(═O)—, —C(═O)— and —C(═S)—;

each R 1 and R 2 is, independently, H, hydroxyl, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, C 5 -C 20 aryl, substituted C 5 -C 20 aryl, a heterocycle radical, a substituted heterocycle radical, heteroaryl, substituted heteroaryl, C 5 -C 7 alicyclic radical, substituted C 5 -C 7 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; and

wherein each substituent group is, independently, halogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 2 -C 12 alkenyl, substituted C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, substituted C 2 -C 12 alkynyl, amino, substituted amino, acyl, substituted acyl, C 1 -C 12 aminoalkyl, C 1 -C 12 aminoalkoxy, substituted C 1 -C 12 aminoalkyl, substituted C 1 -C 12 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, —CH 2 —, —(CH 2 ) 2 —, —CH 2 —O—, —(CH 2 ) 2 —O— or —CH 2 —N(R 3 )—O— wherein R 3 is H or C 1 -C 12 alkyl.

17. The oligomeric compound of claim 12 wherein each bridge group is, independently, —CH 2 —O— or —(CH 2 ) 2 —O—.

18. The oligomeric compound of claim 2 , wherein Nu 1 is O—(CH 2 ) 2 —OCH 3 , Nu 3 is O—(CH 2 ) 2 —OCH 3 , Nu 5 O—(CH 2 ) 2 —OCH 3 , T 1 is H and T 2 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; and

dd. 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.