EXON SKIPPING OLIGOMER CONJUGATES FOR MUSCULAR DYSTROPHY
Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 51 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 51 annealing site in the dystrophin pre-mRNA designated as H51A(+66+95).
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′-CTCCAACATCAAGGAAGATGGCATTTCTAG-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′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′), wherein each thymine (T) is optionally uracil (U).
5 . (canceled)
6 . An antisense oligomer conjugate of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein each Nu from 1 to 30 and 5′ to 3′ is (SEQ ID NO. 1):
Position No. 5′ to 3′
Nu
1
C
2
X
3
C
4
C
5
A
6
A
7
C
8
A
9
X
10
C
11
A
12
A
13
G
14
G
15
A
16
A
17
G
18
A
19
X
20
G
21
G
22
C
23
A
24
X
25
X
26
X
27
C
28
X
29
A
30
G
and wherein A is
C is
G is
and each X is
7 . (canceled)
8 . The antisense oligomer conjugate of claim 6 , wherein the antisense oligomer is of Formula (IIA):
wherein each Nu from 1 to 30 and 5′ to 3′ is (SEQ ID NO. 1):
Position No. 5′ to 3′
Nu
1
C
2
X
3
C
4
C
5
A
6
A
7
C
8
A
9
X
10
C
11
A
12
A
13
G
14
G
15
A
16
A
17
G
18
A
19
X
20
G
21
G
22
C
23
A
24
X
25
X
26
X
27
C
28
X
29
A
30
G
and wherein A is
C is
G is
and X is
9 - 26 . (canceled)
27 . The antisense oligomer conjugate of claim 1 , wherein T is
and
R 1 is C 1 -C 6 alkyl; and
the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′), wherein each thymine (T) is uracil (U).
28 . The antisense oligomer conjugate of claim 1 , wherein T is
and
R 1 is C 1 -C 6 alkyl; and
the targeting sequence is SEQ ID NO: 1
(5'-CTCCAACATCAAGGAAGATGGCATTTCTAG-3').
29 . The antisense oligomer conjugate of claim 1 , wherein T is
and
R 1 is C 1 -C 6 alkyl; and
the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′), wherein each thymine (T) is uracil (U) and the antisense oligomer conjugate is a pharmaceutically acceptable 6HCl salt.
30 . The antisense oligomer conjugate of claim 1 , wherein T is
and
R 1 is C 1 -C 6 alkyl; and the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′) and the antisense oligomer conjugate is a pharmaceutically acceptable 6 HCl salt.
31 . The antisense oligomer conjugate of claim 1 , wherein T is
and
the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′), wherein each thymine (T) is uracil (U).
32 . The antisense oligomer conjugate of claim 1 , wherein T is
and
the targeting sequence is SEQ ID NO: 1
(5'-CTCCAACATCAAGGAAGATGGCATTTCTAG-3').
33 . The antisense oligomer conjugate of claim 1 , wherein T is
and
the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′), wherein each thymine (T) is uracil (U) and the antisense oligomer conjugate is a pharmaceutically acceptable 6HCl salt.
34 . The antisense oligomer conjugate of claim 1 , wherein T is
and
the targeting sequence is SEQ ID NO: 1
(5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′) and the antisense oligomer conjugate is a pharmaceutically acceptable 6HCl salt.
35 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
36 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 27 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
37 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 28 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
38 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 29 and a pharmaceutically acceptable carrier.
39 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 30 and a pharmaceutically acceptable carrier.
40 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 31 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
41 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 32 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
42 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 33 and a pharmaceutically acceptable carrier.
43 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 34 and a pharmaceutically acceptable carrier.