Compound and method for treating myotonic dystrophy

• US 8,835,402 B2
• Filed: 09/26/2013
• Issued: 09/16/2014
• 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 ANN
• Application Number:
  US14/038,314
• Publication Number:
  US 20140107013A1
• Time in Patent Office: 355 Days
• Field of Search: None
• US Class Current: 514/44.A
• 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 for treating myotonic dystrophy DM1, consisting of a 9-base phosphorodiamidate morpholino antisense oligonucleotide,

wherein at least one and up to about 1 per every 2 intersubunit linkage(s) contains a pendant cationic group, and

wherein the 9 bases are complementary to polyCUG repeats in the 3′

UTR region of dystrophia myotonica protein kinase (DMPK) mRNA and have the base sequence of SEQ ID NO;

5 or SEQ ID NO;

9.

2. The antisense compound of claim 1, wherein the cationic group comprises an optionally substituted piperazino group.

3. The antisense compound of claim 1, wherein the oligonucleotide is conjugated to a cell-penetrating peptide.

4. A method of treating myotonic dystrophy DM1 in a mammalian subject, comprising administering to the subject a 9-base phosphorodiamidate morpholino antisense oligonucleotide,

wherein at least one and up to about 1 per every 2 intersubunit linkage(s) contains a pendant cationic group, and

wherein the 9 bases are complementary to polyCUG repeats in the 3′

UTR region of dystrophia myotonica protein kinase (DMPK) mRNA and have the base sequence of SEQ ID NO;

5 or SEQ ID NO;

9,

and repeating said administering at least once every one week to 3 months.

5. The method of claim 4, wherein the cationic group comprises an optionally substituted piperazino group.

6. The method of claim 4, wherein the oligonucleotide is conjugated to a cell-penetrating peptide.

7. The method of claim 4, wherein said administering is by intravenous or subcutaneous injection to the subject, at a dose between 1-20 mg/kg body weight antisense compound.

8. The method of claim 4, wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for improvement in skeletal or heart muscle performance.

9. The method of claim 4, wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for improvement in heart conduction properties.

10. The method of claim 4, wherein said administering is continued at regular intervals of every one to three months, and further includes monitoring the patient during the treatment period for reduction in serum creatine kinase.