Compound and method for treating myotonic dystrophy

• US 10,106,796 B2
• Filed: 08/20/2014
• Issued: 10/23/2018
• Est. Priority Date: 06/26/2009
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Kole, Ryszard, Hanson, Gunnar J.
• Primary Examiner(s): Vivlemore, Tracy
• Application Number:
  US14/464,561
• Publication Number:
  US 20150141321A1
• Time in Patent Office: 1,525 Days
• Field of Search: None
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
• CPC Class Codes: C12N 2310/113 targeting other non-coding nucleic acids, e.g. antagomirs
• CPC Class Codes: C12N 2310/3233 Morpholino-type ring
• CPC Class Codes: C12N 2810/40 Vectors comprising a peptide as targeting moiety, e.g. a synthetic peptide, from undefined source

Abstract

Provided are 9-base morpholino antisense compounds targeted to polyCUG repeats in the 3′UTR region of dystrophia myotonica protein kinase (DMPK) mRNA, and related methods for treating myotonic dystrophy DM1.

Claims

1. An antisense compound, comprising

an uncharged antisense oligomer of 8-30 bases comprising a sequence of at least 8 contiguous bases that is complementary to:

(i) the polyCUG repeats in the 3′

-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in Myotonic dystrophy type 1 (DM1) or (ii) the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in Myotonic dystrophy type 2 (DM2), and

a cell-penetrating peptide (CPP) conjugated to the oligomer, wherein the CPP is of a formula selected from the group consisting of;

2. The antisense compound of claim 1, wherein the CPP is conjugated to the antisense oligomer with a linker selected from glycine (G), cysteine (C), 6-aminohexanoic acid (Ahx), β

-alanine (B), and AhxB.

3. The antisense compound of claim 2, wherein the linker is G.

4. The antisense compound of claim 2, wherein the CPP and linker together are of a formula selected from the group consisting of:

5. The antisense compound of claim 1, wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer (PMO) having a sequence complementary to the polyCUG repeats in the 3′

-UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1.

6. The antisense compound of claim 5, wherein the sequence is selected from SEQ ID NOs:

1-14.

7. The antisense compound of claim 1, wherein the antisense oligomer is a phosphorodiamidate morpholino oligomer (PMO) having a sequence complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in DM2.

8. The antisense compound of claim 7, wherein the sequence is selected from SEQ ID NOs:

19-25.

9. An antisense compound, comprising:

an antisense oligomer of 8-30 morpholino subunits linked together by phosphorodiamidate linkages, wherein;

each morpholino subunit is of a formula;

10. The antisense compound of claim 9, wherein the CPP and linker together are of a formula selected from the group consisting of:

11. The antisense compound of claim 9, wherein the sequence is complementary to the polyCUG repeats in the 3′

UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1.

12. The antisense compound of claim 11, wherein the sequence is selected from SEQ ID NOs:

1-14.

13. The antisense compound of claim 9, wherein the sequence is complementary to the polyCCUG repeats in the first intron of zinc finger protein 9 (ZNF9) mRNA in DM2.

14. The antisense compound of claim 13, wherein the sequence is selected from SEQ ID NOs:

19-25.

15. A method of treating myotonic dystrophy type 1 (DM1) or myotonic dystrophy type 2 (DM2) in a mammalian subject in need thereof, comprising administering to the subject an effective amount of an antisense compound, wherein the antisense compound comprises:

an antisense oligomer of 8-30 morpholino subunits linked together by phosophorodiamidate linkages, wherein;

each morpholino subunit is of a formula;

16. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and an antisense compound, wherein the antisense compound comprises;

an antisense oligomer of 8-30 morpholino subunits linked together by phosphorodiamidate linkages, wherein;

each morpholino subunit is of a formula;