EXON SKIPPING OLIGOMER CONJUGATES FOR MUSCULAR DYSTROPHY
Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 52 skipping are described.
1 . An antisense oligomer conjugate of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each Nu is a nucleobase which taken together form a targeting sequence; and
T is a moiety selected from:
R 1 is C 1 -C 6 alkyl;
wherein the targeting sequence is complementary to an exon 52 annealing site in the dystrophin pre-mRNA designated as H52A(−01+24).
2 . The antisense oligomer conjugate of claim 1 , wherein each Nu is independently selected from cytosine (C), guanine (G), thymine (T), adenine (A), 5-methylcytosine (5 mC), uracil (U), and hypoxanthine (I).
3 . The antisense oligomer conjugate of claim 1 , wherein the targeting sequence is SEQ ID NO: 1 (5′-CTGTTCCAAATCCTGCATTGTTGCC-3′), wherein each thymine (T) is optionally uracil (U).
4 . The antisense oligomer conjugate of claim 1 , wherein T is
and the targeting sequence is SEQ ID NO: 1 (5′-CTGTTCCAAATCCTGCATTGTTGCC-3′), wherein each thymine (T) is optionally uracil (U).
5 . The antisense oligomer conjugate of claim 1 , wherein T is
and the targeting sequence is SEQ ID NO: 1 (5′-CTGTTCCAAATCCTGCATTGTTGCC-3′).
6 . An antisense oligomer conjugate of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein each Nu from 1 to 25 and 5′ to 3′ is:
Position No. 5′ to 3′
Nu
1
C
2
X
3
G
4
X
5
X
6
C
7
C
8
A
9
A
10
A
11
X
12
C
13
C
14
X
15
G
16
C
17
A
18
X
19
X
20
G
21
X
22
X
23
G
24
C
25
C
and wherein A is
C is
G is
and each X is independently
7 . The antisense oligomer conjugate of claim 6 , wherein each X is
8 . The antisense oligomer conjugate of claim 6 , wherein the antisense oligomer is of Formula (IIA):
wherein each Nu from 1 to 25 and 5′ to 3′ is:
Position No. 5′ to 3′
Nu
1
C
2
X
3
G
4
X
5
X
6
C
7
C
8
A
9
A
10
A
11
X
12
C
13
C
14
X
15
G
16
C
17
A
18
X
19
X
20
G
21
X
22
X
23
G
24
C
25
C
and wherein A is
C is
G is
and each X is independently
9 . The antisense oligomer conjugate of claim 8 , wherein each X is
10 - 11 . (canceled)
12 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13 . A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1 .
14 . The method of claim 13 , wherein the antisense oligomer conjugate is administered weekly.
15 . The method of claim 13 , wherein the antisense oligomer conjugate is administered biweekly.
16 . The method of claim 13 , wherein the antisense oligomer conjugate is administered every third week.
17 . The method of claim 13 , wherein the antisense oligomer conjugate is administered monthly.
18 . The method of claim 13 , wherein the antisense oligomer conjugate is administered at a dose selected from about 30 mg/kg, about 40 mg/kg, about 60 mg/kg, about 80 mg/kg, and about 160 mg/kg.
19 - 24 . (canceled)
25 . A method for treating Duchenne muscular dystrophy (DMD) in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
26 . A method of restoring an mRNA reading frame to induce dystrophin production in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
27 . A method of excluding exon 52 from dystrophin pre-mRNA during mRNA processing in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .
28 . A method of binding exon 52 of dystrophin pre-mRNA in a subject having a mutation of the dystrophin gene that is amenable to exon 52 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 12 .