Claims for Patent: 9,758,783

Summary for Patent: 9,758,783

Title:	Antisense molecules and methods for treating pathologies
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.
Inventor(s):	Wilton; Stephen Donald (Applecross, AU), Fletcher; Sue (Bayswater, AU), Adams; Abbie (Kalamunda, AU), Meloni; Penny (Mount Hawthorn, AU)
Assignee:	The University of Western Australia (Crawley, AU)
Application Number:	14/944,886
Patent Claims:	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: (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base, (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; (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 and is uniformly modified to comprise a 5-substituted pyrimidine base; 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 and is uniformly modified to comprise a 5-substituted pyrimidine base; 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: (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 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.