IP Library › Patent Application 18634360
Patent Application
App. No. 18/634,360

EXON SKIPPING OLIGOMERS AND OLIGOMER CONJUGATES FOR MUSCULAR DYSTROPHY

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Quick Facts
Patent No.
US None
App. No.
18/634,360
Abstract

Antisense oligomers and antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 53 skipping are described.

Claims (611)

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 C1-C6 alkyl; and

Z is an integer from 16 to 23,

wherein the targeting sequence is complementary to an exon 53 annealing site in the dystrophin pre-mRNA selected from the group consisting of H53A(+45+62), H53A(+23+42), H53A(+26+45), H53A(+29+48), H53A(+32+51), H53A(+37+56), H53A(+38+57), H53A(+40+59), H53A(+41+60), H53A(+44+63), H53A(+47+66), H53A(+23+43), H53A(+26+46), H53A(+29+49), H53A(+32+52), H53A(+36+56), H53A(+38+58), H53A(+41+61), H53A(+44+64), H53A(+46+66), H53A(+23+44), H53A(+29+50), H53A(+38+59), H53A(+41+62), H53A(+44+65), H53A(+48+69), H53A(+31+53), H53A(+32+54), H53A(+36+58), H53A(+39+61), H53A(+40+62), H53A(+45+67), H53A(+46+68), H53A(+47+69), and H53A(+32+56).

2 . The antisense oligomer conjugate of claim 1 , wherein the annealing site is selected from the group consisting of H53A(+45+62) where Z is 16, H53A(+23+42) where Z is 18, H53A(+26+45) where Z is 18, H53A(+29+48) where Z is 18, H53A(+32+51) where Z is 18, H53A(+37+56) where Z is 18, H53A(+38+57) where Z is 18, H53A(+40+59) where Z is 18, H53A(+41+60) where Z is 18, H53A(+44+63) where Z is 18, H53A(+47+66) where Z is 18, H53A(+23+43) where Z is 19, H53A(+26+46) where Z is 19, H53A(+29+49) where Z is 19, H53A(+32+52) where Z is 19, H53A(+36+56) where Z is 19, H53A(+38+58) where Z is 19, H53A(+41+61) where Z is 19, H53A(+44+64) where Z is 19, H53A(+46+66) where Z is 19, H53A(+23+44) where Z is 20, H53A(+29+50) where Z is 20, H53A(+38+59) where Z is 20, H53A(+41+62) where Z is 20, H53A(+44+65) where Z is 20, H53A(+48+69) where Z is 20, H53A(+31+53) where Z is 21, H53A(+32+54) where Z is 21, H53A(+36+58) where Z is 21, H53A(+39+61) where Z is 21, H53A(+40+62) where Z is 21, H53A(+45+67) where Z is 21, H53A(+46+68) where Z is 21, H53A(+47+69) where Z is 21, and H53A(+32+56) where Z is 23.

3 . The antisense oligomer conjugate of claim 1 , wherein T is

and the targeting sequence and corresponding Z are selected from:

TS

Targeting Sequence (TS)

SEQ

position 1 to Z and

ID

from 5′ to 3′

NO:

Z

i.

GGXGXXCXXGXACXXCAXCC

1

18

ii.

GAAGGXGXXCXXGXACXXCA

2

18

iii.

XCXGAAGGXGXXCXXGXACX

3

18

iv.

GGXXCXGAAGGXGXXCXXGX

4

18

v.

CCXCCGGXXCXGAAGGXGXX

5

18

vi.

GCCXCCGGXXCXGAAGGXGX

6

18

vii.

XXGCCXCCGGXXCXGAAGGX

7

18

viii.

GXXGCCXCCGGXXCXGAAGG

8

18

ix.

ACXGXXGCCXCCGGXXCXGA

9

18

x.

XCAACXGXXGCCXCCGGXXC

10

18

xi.

AGGXGXXCXXGXACXXCAXCC

11

19

xii.

XGAAGGXGXXCXXGXACXXCA

12

19

xiii.

XXCXGAAGGXGXXCXXGXACX

13

19

xiv.

CGGXXCXGAAGGXGXXCXXGX

14

19

xv.

XGCCXCCGGXXCXGAAGGXGX

15

19

xvi.

XGXXGCCXCCGGXXCXGAAGG

16

19

xvii.

AACXGXXGCCXCCGGXXCXGA

17

19

xviii.

XCAACXGXXGCCXCCGGXXCX

18

19

xix.

AAGGXGXXCXXGXACXXCAXCC

19

20

xx.

GXXCXGAAGGXGXXCXXGXACX

20

20

xxi.

XXGCCXCCGGXXCXGAAGGXGX

21

20

xxii.

CXGXXGCCXCCGGXXCXGAAGG

22

20

xxiii.

CAACXGXXGCCXCCGGXXCXGA

23

20

xxiv

CAXXCAACXGXXGCCXCCGGXX

24

20

xxv.

CCGGXXCXGAAGGXGXXCXXGXA

25

21

xxvi.

XCCGGXXCXGAAGGXGXXCXXGX

26

21

xxvii.

XGCCXCCGGXXCXGAAGGXGXXC

27

21

xxviii.

XGXXGCCXCCGGXXCXGAAGGXG

28

21

xxix.

CXGXXGCCXCCGGXXCXGAAGGX

29

21

xxx.

XXCAACXGXXGCCXCCGGXXCXG

30

21

xxxi.

AXXCAACXGXXGCCXCCGGXXCX

31

21

xxxii.

CAXXCAACXGXXGCCXCCGGXXC

32

21

xxxiii.

CCXCCGGXXCXGAAGGXGXXC

33

19

xxxiv.

CCXCCGGXXCXGAAGGXGXXCXXGX

34

23

xxxv.

GXCXXGGCCXCCGXXGXC

35

16

wherein X is thymine (T) or uracil (U).

4 . The antisense oligomer conjugate of claim 3 , wherein each X is independently T.

5 . An antisense oligomer conjugate of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein each Nu is a nucleobase which taken together form a targeting sequence that is complementary to an exon 53 annealing site in the dystrophin pre-mRNA is selected from the group consisting of H53A(+45+62), H53A(+23+42), H53A(+26+45), H53A(+29+48), H53A(+32+51), H53A(+37+56), H53A(+38+57), H53A(+40+59), H53A(+41+60), H53A(+44+63), H53A(+47+66), H53A(+23+43), H53A(+26+46), H53A(+29+49), H53A(+32+52), H53A(+36+56), H53A(+38+58), H53A(+41+61), H53A(+44+64), H53A(+46+66), H53A(+23+44), H53A(+29+50), H53A(+38+59), H53A(+41+62), H53A(+44+65), H53A(+48+69), H53A(+31+53), H53A(+32+54), H53A(+36+58), H53A(+39+61), H53A(+40+62), H53A(+45+67), H53A(+46+68), H53A(+47+69), and H53A(+32+56).

6 . The antisense oligomer conjugate of claim 5 , wherein the annealing site is selected from the group consisting of H53A(+45+62) where Z is 16, H53A(+23+42) where Z is 18, H53A(+26+45) where Z is 18, H53A(+29+48) where Z is 18, H53A(+32+51) where Z is 18, H53A(+37+56) where Z is 18, H53A(+38+57) where Z is 18, H53A(+40+59) where Z is 18, H53A(+41+60) where Z is 18, H53A(+44+63) where Z is 18, H53A(+47+66) where Z is 18, H53A(+23+43) where Z is 19, H53A(+26+46) where Z is 19, H53A(+29+49) where Z is 19, H53A(+32+52) where Z is 19, H53A(+36+56) where Z is 19, H53A(+38+58) where Z is 19, H53A(+41+61) where Z is 19, H53A(+44+64) where Z is 19, H53A(+46+66) where Z is 19, H53A(+23+44) where Z is 20, H53A(+29+50) where Z is 20, H53A(+38+59) where Z is 20, H53A(+41+62) where Z is 20, H53A(+44+65) where Z is 20, H53A(+48+69) where Z is 20, H53A(+31+53) where Z is 21, H53A(+32+54) where Z is 21, H53A(+36+58) where Z is 21, H53A(+39+61) where Z is 21, H53A(+40+62) where Z is 21, H53A(+45+67) where Z is 21, H53A(+46+68) where Z is 21, H53A(+47+69) where Z is 21, and H53A(+32+56) where Z is 23.

7 . The antisense oligomer conjugate of claim 5 , wherein the targeting sequence and corresponding Z are selected from:

TS

Targeting Sequence (TS)

SEQ

position t to Z

ID

and from 5′ to 3′

NO:

Z

i.

GGXGXXCXXGXACXXCAXCC

1

18

ii.

GAAGGXGXXCXXGXACXXCA

2

18

iii.

XCXGAAGGXGXXCXXGXACX

3

18

iv.

GGXXCXGAAGGXGXXCXXGX

4

18

v.

CCXCCGGXXCXGAAGGXGXX

5

18

vi.

GCCXCCGGXXCXGAAGGXGX

6

18

vii.

XXGCCXCCGGXXCXGAAGGX

7

18

viii.

GXXGCCXCCGGXXCXGAAGG

8

18

ix.

ACXGXXGCCXCCGGXXCXGA

9

18

x.

XCAACXGXXGCCXCCGGXXC

10

18

xi.

AGGXGXXCXXGXACXXCAXCC

11

19

xii.

XGAAGGXGXXCXXGXACXXCA

12

19

xiii.

XXCXGAAGGXGXXCXXGXACX

13

19

xiv.

CGGXXCXGAAGGXGXXCXXGX

14

19

xv.

XGCCXCCGGXXCXGAAGGXGX

15

19

xvi.

XGXXGCCXCCGGXXCXGAAGG

16

19

xvii.

AACXGXXGCCXCCGGXXCXGA

17

19

xviii.

XCAACXGXXGCCXCCGGXXCX

18

19

xix.

AAGGXGXXCXXGXACXXCAXCC

19

20

xx.

GXXCXGAAGGXGXXCXXGXACX

20

20

xxi.

XXGCCXCCGGXXCXGAAGGXGX

21

20

xxii.

CXGXXGCCXCCGGXXCXGAAGG

22

20

xxiii.

CAACXGXXGCCXCCGGXXCXGA

23

20

xxiv.

CAXXCAACXGXXGCCXCCGGXX

24

20

xxv.

CCGGXXCXGAAGGXGXXCXXGXA

25

21

xxvi.

XCCGGXXCXGAAGGXGXXCXXGX

26

21

xxvii.

XGCCXCCGGXXCXGAAGGXGXXC

27

21

xxviii.

XGXXGCCXCCGGXXCXGAAGGXG

28

21

xxix.

CXGXXGCCXCCGGXXCXGAAGGX

29

21

xxx.

XXCAACXGXXGCCXCCGGXXCXG

30

21

xxxi.

AXXCAACXGXXGCCXCCGGXXCX

31

21

xxxii.

CAXXCAACXGXXGCCXCCGGXXC

32

21

xxxiii.

CCXCCGGXXCXGAAGGXGXXC

33

19

xxxiv.

CCXCCGGXXCXGAAGGXGXXCXXGX

34

23

xxxv.

GXCXXGGCCXCCGXXGXC

35

16

wherein A is

 C is

 G is

 and X is

8 . The antisense oligomer conjugate of claim 7 , wherein each X is independently

9 . An antisense oligomer of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

each Nu is a nucleobase which taken together form a targeting sequence;

T is a moiety selected from:

R 1 is C1-C6 alkyl; and

R 2 is selected from H or acetyl,

wherein the targeting sequence is complementary to an exon 53 annealing site in the dystrophin pre-mRNA selected from the group consisting of H53A(+23+42), H53A(+26+45), H53A(+29+48), H53A(+32+51), H53A(+37+56), H53A(+38+57), H53A(+40+59), H53A(+41+60), H53A(+44+63), H53A(+47+66), H53A(+23+43), H53A(+26+46), H53A(+29+49), H53A(+32+52), H53A(+38+58), H53A(+41+61), H53A(+44+64), H53A(+46+66), H53A(+23+44), H53A(+29+50), H53A(+38+59), H53A(+41+62), H53A(+44+65), H53A(+31+53), H53A(+32+54), H53A(+36+58), H53A(+39+61), H53A(+40+62), H53A(+45+67), H53A(+46+68), and H53A(+47+69).

10 . The antisense oligomer of claim 9 , wherein the annealing site is selected from the group consisting of H53A(+23+42) where Z is 18, H53A(+26+45) Z is 18, H53A(+29+48) Z is 18, H53A(+32+51) Z is 18, H53A(+37+56) Z is 18, H53A(+38+57) Z is 18, H53A(+40+59) Z is 18, H53A(+41+60) Z is 18, H53A(+44+63) Z is 18, H53A(+47+66) Z is 18, H53A(+23+43) where Z is 19, H53A(+26+46) where Z is 19, H53A(+29+49) where Z is 19, H53A(+32+52) where Z is 19, H53A(+38+58) where Z is 19, H53A(+41+61) where Z is 19, H53A(+44+64) where Z is 19, H53A(+46+66) where Z is 19, H53A(+23+44) where Z is 20, H53A(+29+50) where Z is 20, H53A(+38+59) where Z is 20, H53A(+41+62) where Z is 20, H53A(+44+65) where Z is 20, H53A(+31+53) where Z is 21, H53A(+32+54) where Z is 21, H53A(+36+58) where Z is 21, H53A(+39+61) where Z is 21, H53A(+40+62) where Z is 21, H53A(+45+67) where Z is 21, H53A(+46+68) where Z is 21, and H53A(+47+69) where Z is 21.

11 . The antisense oligomer of claim 9 , wherein T is

and the targeting sequence and corresponding Z are selected from:

TS

Targeting Sequence (TS)

SEQ

position 1 to Z 

ID

and from 5′ to 3′

NO:

Z

i.

GGXGXXCXXGXACXXCAXCC

1

18

ii.

GAAGGXGXXCXXGXACXXCA

2

18

iii.

XCXGAAGGXGXXCXXGXACX

3

18

iv.

GGXXCXGAAGGXGXXCXXGX

4

18

v.

CCXCCGGXXCXGAAGGXGXX

5

18

vi.

GCCXCCGGXXCXGAAGGXGX

6

18

vii.

XXGCCXCCGGXXCXGAAGGX

7

18

viii.

GXXGCCXCCGGXXCXGAAGG

8

18

ix.

ACXGXXGCCXCCGGXXCXGA

9

18

x.

XCAACXGXXGCCXCCGGXXC

10

18

xi.

AGGXGXXCXXGXACXXCAXCC

11

19

xii.

XGAAGGXGXXCXXGXACXXCA

12

19

xiii.

XXCXGAAGGXGXXCXXGXACX

13

19

xiv.

CGGXXCXGAAGGXGXXCXXGX

14

19

xv.

XGCCXCCGGXXCXGAAGGXGX

15

19

xvi.

XGXXGCCXCCGGXXCXGAAGG

16

19

xvii.

AACXGXXGCCXCCGGXXCXGA

17

19

xviii.

XCAACXGXXGCCXCCGGXXCX

18

19

xix.

AAGGXGXXCXXGXACXXCAXCC

19

20

xx.

GXXCXGAAGGXGXXCXXGXACX

20

20

xxi.

XXGCCXCCGGXXCXGAAGGXGX

21

20

xxii

CXGXXGCCXCCGGXXCXGAAGG

22

20

xxiii.

CAACXGXXGCCXCCGGXXCXGA

23

20

xxiv.

CCGGXXCXGAAGGXGXXCXXGXA

25

21

xxv.

XCCGGXXCXGAAGGXGXXCXXGX

26

21

xxvi.

XGCCXCCGGXXCXGAAGGXGXXC

27

21

xxvii.

XGXXGCCXCCGGXXCXGAAGGXG

28

21

xxviii.

CXGXXGCCXCCGGXXCXGAAGGX

29

21

xxix.

XXCAACXGXXGCCXCCGGXXCXG

30

21

xxx.

AXXCAACXGXXGCCXCCGGXXCX

31

21

xxxi.

CAXXCAACXGXXGCCXCCGGXXC

32

21

wherein X is thymine (T) or uracil (U).

12 . The antisense oligomer of claim 11 , wherein each X is T.

13 . An antisense oligomer of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein:

R is selected from H or acetyl; and

each Nu is a nucleobase which taken together form a targeting sequence that is complementary to an exon 53 annealing site in the dystrophin pre-mRNA selected from the group consisting of H53A(+23+42), H53A(+26+45), H53A(+29+48), H53A(+32+51), H53A(+37+56), H53A(+38+57), H53A(+40+59), H53A(+41+60), H53A(+44+63), H53A(+47+66), H53A(+23+43), H53A(+26+46), H53A(+29+49), H53A(+32+52), H53A(+38+58), H53A(+41+61), H53A(+44+64), H53A(+46+66), H53A(+23+44), H53A(+29+50), H53A(+38+59), H53A(+41+62), H53A(+44+65), H53A(+31+53), H53A(+32+54), H53A(+36+58), H53A(+39+61), H53A(+40+62), H53A(+45+67), H53A(+46+68), and H53A(+47+69).

14 . The antisense oligomer of claim 13 , wherein the annealing site is selected from the group consisting of H53A(+23+42) where Z is 18, H53A(+26+45) Z is 18, H53A(+29+48) Z is 18, H53A(+32+51) Z is 18, H53A(+37+56) Z is 18, H53A(+38+57) Z is 18, H53A(+40+59) Z is 18, H53A(+41+60) Z is 18, H53A(+44+63) Z is 18, H53A(+47+66) Z is 18, H53A(+23+43) where Z is 19, H53A(+26+46) where Z is 19, H53A(+29+49) where Z is 19, H53A(+32+52) where Z is 19, H53A(+38+58) where Z is 19, H53A(+41+61) where Z is 19, H53A(+44+64) where Z is 19, H53A(+46+66) where Z is 19, H53A(+23+44) where Z is 20, H53A(+29+50) where Z is 20, H53A(+38+59) where Z is 20, H53A(+41+62) where Z is 20, H53A(+44+65) where Z is 20, H53A(+31+53) where Z is 21, H53A(+32+54) where Z is 21, H53A(+36+58) where Z is 21, H53A(+39+61) where Z is 21, H53A(+40+62) where Z is 21, H53A(+45+67) where Z is 21, H53A(+46+68) where Z is 21, and H53A(+47+69) where Z is 21.

15 . The antisense oligomer of claim 13 , wherein the targeting sequence and corresponding Z are selected from:

TS

Targeting Sequence (TS)

SEQ

position 1 to Z and

ID

from 5′ to 3′

NO:

Z

i.

GGXGXXCXXGXACXXCAXCC

1

18

ii.

GAAGGXGXXCXXGXACXXCA

2

18

iii.

XCXGAAGGXGXXCXXGXACX

3

18

iv.

GGXXCXGAAGGXGXXCXXGX

4

18

v.

CCXCCGGXXCXGAAGGXGXX

5

18

vi.

GCCXCCGGXXCXGAAGGXGX

6

18

vii.

XXGCCXCCGGXXCXGAAGGX

7

18

viii.

GXXGCCXCCGGXXCXGAAGG

8

18

ix.

ACXGXXGCCXCCGGXXCXGA

9

18

x.

XCAACXGXXGCCXCCGGXXC

10

18

xi.

AGGXGXXCXXGXACXXCAXCC

11

19

xii.

XGAAGGXGXXCXXGXACXXCA

12

19

xiii.

XXCXGAAGGXGXXCXXGXACX

13

19

xiv.

CGGXXCXGAAGGXGXXCXXGX

14

19

xv.

XGCCXCCGGXXCXGAAGGXGX

15

19

xvi

XGXXGCCXCCGGXXCXGAAGG

16

19

xvii.

AACXGXXGCCXCCGGXXCXGA

17

19

xviii.

XCAACXGXXGCCXCCGGXXCX

18

19

xix.

AAGGXGXXCXXGXACXXCAXCC

19

20

xx.

GXXCXGAAGGXGXXCXXGXACX

20

20

xxi.

XXGCCXCCGGXXCXGAAGGXGX

21

20

xxii.

CXGXXGCCXCCGGXXCXGAAGG

22

20

xxiii.

CAACXGXXGCCXCCGGXXCXGA

23

20

xxiv.

CCGGXXCXGAAGGXGXXCXXGXA

25

21

xxv.

XCCGGXXCXGAAGGXGXXCXXGX

26

21

xxvi.

XGCCXCCGGXXCXGAAGGXGXXC

27

21

xxvii.

XGXXGCCXCCGGXXCXGAAGGXG

28

21

xxviii.

CXGXXGCCXCCGGXXCXGAAGGX

29

21

xxix.

XXCAACXGXXGCCXCCGGXXCXG

30

21

xxx.

AXXCAACXGXXGCCXCCGGXXCX

31

21

xxxi.

CAXXCAACXGXXGCCXCCGGXXC

32

21

wherein A is

 C is

 G is

 and X is

16 . The antisense oligomer of claim 15 , wherein each X is independently

17 . A pharmaceutical composition, comprising an antisense oligomer conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18 . 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 53 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1 .

19 . 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 53 skipping, the method comprising administering to the subject the antisense oligomer conjugate of claim 1 .

20 . 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 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 17 .

21 . 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 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 17 .

22 . A method of excluding exon 53 from dystrophin pre-mRNA during mRNA processing in a subject having a mutation of the dystrophin gene that is amenable to exon 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 17 .

23 . A method of binding exon 53 of dystrophin pre-mRNA in a subject having a mutation of the dystrophin gene that is amenable to exon 53 skipping, the method comprising administering to the subject the pharmaceutical composition of claim 17 .

Assignments (2)
SECURITY INTEREST Recorded May 7, 2025
From: SAREPTA THERAPEUTICS, INC.
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 071218/0445 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 27, 2025
From: SCHNELL, FREDERICK JOSEPH; WU, CHIA-LING
To: SAREPTA THERAPEUTICS, INC.
Reel/Frame 070353/0242 →