Systemic delivery of myostatin short interfering nucleic acids (siNA) conjugated to a lipophilic moiety

• US 10,004,814 B2
• Filed: 11/10/2014
• Issued: 06/26/2018
• Est. Priority Date: 11/11/2013
• Status: Active Grant

• Current Assignee: Sirna Therapeutics, Inc. (Alnylam Pharmaceuticals Incorporated)
• Original Assignee: Sirna Therapeutics, Inc. (Alnylam Pharmaceuticals Incorporated)
• Inventors: Tadin-Strapps, Marija, Khan, Tayeba, Strapps, Walter Richard, Sepp-Lorenzino, Laura, Jadhav, Vasant, Brown, Duncan
• Primary Examiner(s): Whiteman, Brian A
• Application Number:
  US15/035,950
• Publication Number:
  US 20160256570A1
• Time in Patent Office: 1,324 Days
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 48/0058 Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/06 Anabolic agents androgens A61P5/26
• CPC Class Codes: C12N 15/1136 against growth factors, growth regulators, cytokines, lymphokines or hormones
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol

Abstract

The present invention provides methods comprising the in vivo delivery of small nucleic acid molecules capable of mediating RNA interference and reducing the expression of myostatin, wherein the small nucleic acid molecules are introduced to a subject by systemic administration. Specifically, the invention relates to methods comprising the in vivo delivery of short interfering nucleic acid (siNA) molecules that target a myostatin gene expressed by a subject, wherein the siNA molecule is conjugated to a lipophilic moiety, such as cholesterol. The myostatin siNA conjugates that are delivered as per the methods disclosed are useful to modulate the in vivo expression of myostatin, increase muscle mass and/or enhance muscle performance. Use of the disclosed methods is further indicated for treating musculoskeletal diseases or disorders and/or diseases or disorders that result in conditions in which muscle is adversely affected.

Claims

1. A double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of myostatin, wherein:

(a) the siNA comprises a sense strand and an antisense strand;

(b) each strand is independently 19 to 30 nucleotides in length; and

(c) the antisense strand comprises nucleotide sequence of;

2. A double-stranded siNA molecule of claim 1, wherein the siNA molecule comprises:

3. The double-stranded siNA molecule of claim 2, wherein the siNA molecule is linked to a lipophilic moiety.

4. The double-stranded siNA molecule of claim 3, wherein the lipophilic moiety is cholesterol.

5. The double-stranded siNA molecule of claim 4, wherein the lipophilic moiety is attached to a 3′

-end of the siNA molecule.

6. The double-stranded siNA molecule of claim 4, wherein the lipophilic moiety is attached to a 5′

-end of the siNA molecule.

7. The double-stranded siNA molecule of claim 2, which comprises one or more chemically-modified nucleotides.

8. The double-stranded siNA molecule of claim 2, which comprises one or more 3′

-overhanging nucleotides on one or both strands.

9. The double-stranded siNA molecule of claim 1, wherein the siNA molecule is linked to a lipophilic moiety.

10. The double-stranded siNA molecule of claim 9, wherein the lipophilic moiety is cholesterol.

11. The double-stranded siNA molecule of claim 10, wherein the lipophilic moiety is attached to a 3′

-end of the siNA molecule.

12. The double-stranded siNA molecule of claim 10, wherein the lipophilic moiety is attached to a 5′

-end of the siNA molecule.

13. The double-stranded siNA molecule of claim 1, which comprises one or more chemically-modified nucleotides.

14. The double-stranded siNA molecule of claim 1, which comprises one or more 3′

-overhanging nucleotides on one or both strands.