IP Library › Granted Patent US 11,447,776
Granted Patent B2
US 11,447,776 · App. 16/993,116 · Granted Sep 20, 2022

Antisense molecules and methods for treating pathologies

Inventors: Stephen Donald Wilton (Applecross, AU); Sue Fletcher (Bayswater, AU); Abbie Adams (Kalamunda, AU); Penny Meloni (Mount Hawthorn, AU)
Assignee: The University of Western Australia
C12N15/113C12N15/111C12N2310/11C12N2310/315C12N2310/3181C12N2310/321C12N2310/3233C12N2310/351C12N2320/33
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Quick Facts
Patent No.
US 11,447,776
App. No.
16/993,116
Granted
Sep 20, 2022
Kind
B2
Abstract

An antisense molecule capable of binding to a selected target site to induce exon skipping in the dystrophin gene, as set forth in SEQ ID NO: 1 to 59.

Claims (36)

1. An antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof.

2. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

3. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain.

4. An antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping.

5. The antisense oligonucleotide of claim 4 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

6. The antisense oligonucleotide of claim 4 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

7. A pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping.

8. The pharmaceutically acceptable salt of an antisense oligonucleotide of claim 7 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

9. The pharmaceutically acceptable salt of an antisense oligonucleotide claim 7 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

10. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

11. The method of claim 10 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

12. The method of claim 10 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain.

13. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

14. The method of claim 13 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

15. The method of claim 14 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

16. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 exon 9 skipping, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

17. The method of claim 16 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

18. The method of claim 16 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

19. A pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

21. The pharmaceutical composition of claim 19 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain.

22. A pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

24. The pharmaceutical composition of claim 22 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

25. A pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

27. The pharmaceutical composition of claim 25 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

28. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

29. The method of claim 28 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

30. The method of claim 28 , wherein the antisense oligonucleotide or pharmaceutically acceptable salt thereof is chemically linked to a polyethylene glycol chain.

31. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

32. The method of claim 31 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

33. The method of claim 31 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

34. A method for restoring an mRNA reading frame to induce dystrophin protein production in a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 8 and exon 9 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 25 bases in length, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(+42+66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 and exon 9 skipping, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

35. The method of claim 34 , wherein the antisense oligonucleotide is chemically linked to one or more moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the oligonucleotide.

36. The method of claim 34 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2022
From: WILTON, STEPHEN DONALD; FLETCHER, SUE; ADAMS, ABBIE; MELONI, PENNY
To: THE UNIVERSITY OF WESTERN AUSTRALIA
Reel/Frame 059946/0587 →
Priority Claims (1)
AU 2009905549 · Nov 12, 2009 · national
Continuity (6)
Continuation 16357918 · Mar 19, 2019
Division 15661750 · Jul 27, 2017
Continuation 14944886 · Nov 18, 2015
Continuation 14108137 · Dec 16, 2013
Continuation 13509331
Related Publication 20210040482A1 · Feb 11, 2021
Cited By (1)
US 12,709,749