Nucleic acid polypeptide compositions and methods for inducing exon skipping

Abstract

To provide nucleic acid-polypeptide compositions and methods for inducing exon skipping.SOLUTION: Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein are methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.SELECTED DRAWING: Figure 3

Claims

1. A polynucleic acid conjugate comprising an anti-human transferrin receptor antibody and at least one polynucleic acid molecule, wherein the at least one polynucleic acid molecule comprises at least one phosphorodiamidate morpholinooligonucleotide (PMO)-modified non-natural nucleotide, and the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1056-1067, 1079, 1081-1082, 1085-1087, and 1089.

2. The polynucleic acid conjugate according to claim 1, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1056 to 1067.

3. The polynucleic acid conjugate according to claim 1, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1079, 1081-1082, 1085-1087, and 1089.

4. The polynucleic acid conjugate according to claim 1, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1063 and 1086.

5. The polynucleic acid conjugate according to claim 1, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from SEQ ID NO: 1063.

6. The aforementioned polynucleic acid conjugate, A-(X １ -B) ｎ Formula (V) Including, in the formula, A comprises the anti-human transferrin receptor antibody, B consists of at least one polynucleic acid molecule, X １ It consists of a bond or a first nonpolymer linker, n is the average value selected from 1 to 12. A polynucleic acid conjugate according to any one of claims 1 to 5.

7. The polynucleic acid conjugate according to any one of claims 1 to 6, wherein the at least one polynucleic acid molecule is a single-stranded oligonucleotide.

8. The polynucleic acid conjugate according to any one of claims 1 to 7, wherein the at least one polynucleic acid molecule comprises at least one modified internucleotide bond, at least one reverse debase moiety, at least one 5'-vinylphosphonate modified non-natural nucleotide, or a combination thereof.

9. A pharmaceutical composition for treating a disease or illness characterized by a deficient DMD mRNA in a subject requiring treatment for such a disease or illness, comprising an anti-human transferrin receptor antibody and a polynucleic acid conjugate comprising at least one polynucleic acid molecule, wherein the at least one polynucleic acid molecule comprises at least one non-natural nucleotide modified with a phosphorodiamidate morpholinooligonucleotide (PMO), and the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1056-1067, 1079, 1081-1082, 1085-1087, and 1089.

10. The pharmaceutical composition according to claim 9, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1056 to 1067.

11. The pharmaceutical composition according to claim 9, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1079, 1081-1082, 1085-1087, and 1089.

12. The pharmaceutical composition according to claim 9, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from a nucleic acid sequence selected from SEQ ID NO: 1063 and 1086.

13. The pharmaceutical composition according to claim 9, wherein the at least one polynucleic acid molecule comprises at least 26 consecutive nucleotides from SEQ ID NO: 1063.

14. The pharmaceutical composition according to any one of claims 9-13, wherein the disease or illness is Duchenne muscular dystrophy.

15. The pharmaceutical composition according to any one of claims 9-14, wherein the subject is a human.

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