IP Library › Granted Patent US 9,758,783

Granted Patent B2

US 9,758,783 · App. 14/944,886 · Granted Sep 12, 2017

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

C12N15/113 C12N15/111 C12N2310/11 C12N2310/3233 C12N2310/351 C12N2320/33

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Quick Facts

Patent No.: US 9,758,783
App. No.: 14/944,886
Granted: Sep 12, 2017
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

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 (107)

1. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:

(i) an antisense oligonucleotide of 34 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−09+25), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(ii) an antisense oligonucleotide of 28 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−03+25), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(iii) an antisense oligonucleotide of 31 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−06+25), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(iv) an antisense oligonucleotide of 31 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−12+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(v) an antisense oligonucleotide of 22 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−03+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(vi) an antisense oligonucleotide of 28 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−09+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(vii) an antisense oligonucleotide of 28 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−12+16), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(viii) an antisense oligonucleotide of 39 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−14+25), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(ix) an antisense oligonucleotide of 27 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−08+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(x) an antisense oligonucleotide of 32 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−07+25), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xi) an antisense oligonucleotide of 34 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−12+22), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xii) an antisense oligonucleotide of 31 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−09+22), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xiii) an antisense oligonucleotide of 39 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−09+30), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xiv) an antisense oligonucleotide of 28 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−06+22), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xv) an antisense oligonucleotide of 34 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−06+28), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

(xvi) an antisense oligonucleotide of 25 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−03+22), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping; and

(xvii) an antisense oligonucleotide of 31 bases in length 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A (−03+28), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping;

or a pharmaceutically acceptable salt thereof,

thereby treating the patient.

2. The method of claim 1 , 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 antisense oligonucleotide.

3. The method of claim 1 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

4. The method of claim 1 , wherein the antisense oligonucleotide is administered intravenously.

5. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:

or a pharmaceutically acceptable salt thereof,

thereby treating the patient.

6. The method of claim 5 , 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 antisense oligonucleotide.

7. The method of claim 5 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

8. The method of claim 5 , wherein the antisense oligonucleotide is administered intravenously.

9. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutical composition comprising: (i) antisense oligonucleotide selected from the group consisting of:

(i) an antisense oligonucleotide of 34 bases comprising the base sequence GCU GCC CAA UGC CAU CCU GGA GUU CCU GUA AGA U (SEQ ID NO: 11), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(ii) an antisense oligonucleotide of 28 bases comprising the base sequence GCU GCC CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 55), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(iii) an antisense oligonucleotide of 31 bases comprising the base sequence GCU GCC CAA UGC CAU CCU GGA GUU CCU GUA A (SEQ ID NO: 61), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(iv) an antisense oligonucleotide of 31 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU GUA AGA UAC C (SEQ ID NO: 62), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(v) an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(vi) an antisense oligonucleotide of 28 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU GUA AGA U (SEQ ID NO: 64), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(vii) an antisense oligonucleotide of 28 bases comprising the base sequence UGC CAU CCU GGA GUU CCU GUA AGA UAC C (SEQ ID NO: 66), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(viii) an antisense oligonucleotide of 39 bases comprising the base sequence GCU GCC CAA UGC CAU CCU GGA GUU CCU GUA AGA UAC CAA (SEQ ID NO: 236), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(ix) an antisense oligonucleotide of 27 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU GUA AGA (SEQ ID NO: 230), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(x) an antisense oligonucleotide of 34 bases comprising the base sequence GCC CAA UGC CAU CCU GGA GUU CCU GUA AGA UAC C (SEQ ID NO: 237), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xi) an antisense oligonucleotide of 31 bases comprising the base sequence GCC CAA UGC CAU CCU GGA GUU CCU GUA AGA U (SEQ ID NO: 239), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xii) an antisense oligonucleotide of 39 bases comprising the base sequence UUG CCG CUG CCC AAU GCC AUC CUG GAG UUC CUG UAA GAU (SEQ ID NO: 240), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xiii) an antisense oligonucleotide of 32 bases comprising the base sequence GCU GCC CAA UGC CAU CCU GGA GUU CCU GUA AG (SEQ ID NO: 241), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xiv) an antisense oligonucleotide of 28 bases comprising the base sequence GCC CAA UGC CAU CCU GGA GUU CCU GUA A (SEQ ID NO: 242), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xv) an antisense oligonucleotide of 34 bases comprising the base sequence GCC GCU GCC CAA UGC CAU CCU GGA GUU CCU GUA A (SEQ ID NO: 243), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

(xvi) an antisense oligonucleotide of 25 bases comprising the base sequence GCC CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 244), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain; and

(xvii) an antisense oligonucleotide of 31 bases comprising the base sequence GCC GCU GCC CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 245), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;

or a pharmaceutically acceptable salt thereof;

and (ii) a pharmaceutically acceptable carrier,

thereby treating the patient.

10. The method of claim 9 , wherein the antisense oligonucleotide is administered intravenously.

11. 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 45 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:

or a pharmaceutically acceptable salt thereof,

thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

12. The method of claim 11 , 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 antisense oligonucleotide.

13. The method of claim 11 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

14. The method of claim 11 , wherein the antisense oligonucleotide is administered intravenously.

15. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby treating the patient.

16. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby treating the patient.

17. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutically acceptable salt of an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby treating the patient.

18. 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 45 skipping, comprising administering to the patient an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

19. 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 45 skipping, comprising administering to the patient an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

20. 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 45 skipping, comprising administering to the patient a pharmaceutically acceptable salt of an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

21. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby treating the patient.

22. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby treating the patient.

23. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby treating the patient.

24. 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 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

25. 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 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

26. 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 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) a pharmaceutically acceptable salt of an antisense oligonucleotide of 22 bases comprising the base sequence CAA UGC CAU CCU GGA GUU CCU G (SEQ ID NO: 63), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, wherein the antisense oligonucleotide is uniformly modified to comprise a 5-substituted pyrimidine base, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain, and (ii) a pharmaceutically acceptable carrier, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient.

27. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient an antisense oligonucleotide of 22 bases in length, or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A(−03+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping, thereby treating the patient.

28. The method of claim 27 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

29. A method for treating a patient with Duchenne muscular dystrophy (DMD) in need thereof who has a mutation of the DMD gene that is amenable to exon 45 skipping, comprising administering to the patient a pharmaceutical composition comprising (i) an antisense oligonucleotide of 22 bases in length, or a pharmaceutically acceptable salt thereof, wherein the antisense oligonucleotide is 100% complementary to a target region of exon 45 of the human dystrophin pre-mRNA, wherein the target region is annealing site H45A(−03+19), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 45 skipping, and (ii) a pharmaceutically acceptable carrier, thereby treating the patient.

30. The method of claim 29 , wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 16, 2015

From: WILTON, STEPHEN DONALD; FLETCHER, SUE; ADAMS, ABBIE; MELONI, PENNY

To: THE UNIVERSITY OF WESTERN AUSTRALIA

Reel/Frame 037303/0297 →

Priority Claims (1)

AU 2009905549 · Nov 12, 2009 · national

Continuity (3)

Continuation 14108137 · Dec 16, 2013

Continuation 13509331

Related Publication 20160177301A1 · Jun 23, 2016