Antisense oligonucleotides for inducing exon skipping and methods of use thereof
First Claim
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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 8 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:
- (i) an antisense oligonucleotide of 24 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;
(ii) an antisense oligonucleotide of 21 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A (−
03+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;
(iii) an antisense oligonucleotide of 25 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
07+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;
(iv) an antisense oligonucleotide of 20 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+14), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;
or a pharmaceutically acceptable salt thereof,thereby treating the patient.
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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 214.
240 Citations
14 Claims
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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 8 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:
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(i) an antisense oligonucleotide of 24 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(ii) an antisense oligonucleotide of 21 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A (−
03+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(iii) an antisense oligonucleotide of 25 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
07+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(iv) an antisense oligonucleotide of 20 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+14), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;or a pharmaceutically acceptable salt thereof, thereby treating the patient. - View Dependent Claims (2, 3, 4)
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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 8 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:
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(i) an antisense oligonucleotide of 24 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG UAA (SEQ ID NO;
1), in which the uracil bases are thymine bases and wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide;(ii) an antisense oligonucleotide of 21 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG (SEQ ID NO;
2), in which the uracil bases are thymine bases and wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide;(iii) an antisense oligonucleotide of 25 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG UAA G (SEQ ID NO;
3), in which the uracil bases are thymine bases and wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide;(iv) an antisense oligonucleotide of 20 bases comprising the base sequence GGU GGU AUC AAC AUC UGU AA (SEQ ID NO;
4), in which the uracil bases are thymine bases and wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide;or a pharmaceutically acceptable salt thereof, thereby treating the patient. - View Dependent Claims (6, 7, 8)
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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 8 skipping, comprising administering to the patient a pharmaceutical composition comprising:
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(a) an antisense oligonucleotide selected from the group consisting of; (i) an antisense oligonucleotide of 24 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG UAA (SEQ ID NO;
1), in which the uracil bases are thymine bases, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;(ii) an antisense oligonucleotide of 21 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG (SEQ ID NO;
2), in which the uracil bases are thymine bases, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;(iii) an antisense oligonucleotide of 25 bases comprising the base sequence GAU AGG UGG UAU CAA CAU CUG UAA G (SEQ ID NO;
3), in which the uracil bases are thymine bases, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;(iv) an antisense oligonucleotide of 20 bases comprising the base sequence GGU GGU AUC AAC AUC UGU AA (SEQ ID NO;
4), in which the uracil bases are thymine bases, wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide is chemically linked to a polyethylene glycol chain;or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, thereby treating the patient. - View Dependent Claims (10)
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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 8 skipping, comprising administering to the patient an antisense oligonucleotide selected from the group consisting of:
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(i) an antisense oligonucleotide of 24 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(ii) an antisense oligonucleotide of 21 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A (−
03+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(iii) an antisense oligonucleotide of 25 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
07+18), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;(iv) an antisense oligonucleotide of 20 bases in length 100% complementary to a target region of exon 8 of the human dystrophin pre-mRNA, wherein the target region is annealing site H8A(−
06+14), wherein the antisense oligonucleotide is a morpholino antisense oligonucleotide, and wherein the antisense oligonucleotide specifically hybridizes to the annealing site inducing exon 8 skipping;or a pharmaceutically acceptable salt thereof, thereby restoring the mRNA reading frame to induce dystrophin protein production in the patient. - View Dependent Claims (12, 13, 14)
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Specification