KR-20260066066-A - Composition and method for treating sarcopenia

Abstract

The present disclosure provides a composition and a method for treating sarcopenia, including age-related sarcopenia. Various embodiments include an inhibitory nucleic acid, a composition comprising an inhibitory nucleic acid, and a method for treating such disorders using an inhibitory nucleic acid.

Inventors

• 네르 안데르스 마이클
• 볼드리지 멜리사 앤

Assignees

• 더 리젠츠 오브 더 유니버시티 오브 캘리포니아

Dates

Publication Date

20260512

Application Date

20240909

Priority Date

20230907

Claims (20)

1. A method for treating age-related sarcopenia, comprising the step of administering an effective amount of a miR-128 inhibitor to an individual diagnosed with age-related sarcopenia.
2. A method according to claim 1, wherein the individual is not diagnosed with a metabolic disorder.
3. A method according to claim 1 or 2, wherein the miR-128 inhibitor comprises an inhibitory nucleic acid.
4. In paragraph 3, the method wherein the inhibitory nucleic acid comprises one or more of the following sequences: 5'-ACCGGTTCACTGTG-3' (Sequence No.: 1); 5'-GACCGGTTCACTGT-3' (Sequence No.: 2); and 5'-AGACCGGTTCACTGTG-3' (Sequence No.: 3).
5. A method according to claim 3 or 4, wherein the inhibitory nucleic acid comprises one or more lock nucleic acids (LNA).
6. A method according to any one of claims 2 to 5, wherein the inhibitory nucleic acid comprises one or more of a modified backbone and one or more of one or more 5-methyldeoxycytosine residues.
7. A method according to any one of claims 2 to 6, wherein the inhibitory nucleic acid has a length of 14 to 20 nucleotides.
8. A method according to any one of claims 2 to 7, wherein the inhibitory nucleic acid comprises a nucleotide sequence designated as "NRC-0090".
9. A method according to any one of claims 2 to 7, wherein the inhibitory nucleic acid comprises a nucleotide sequence designated as "NRC-0091".
10. A method according to any one of claims 2 to 7, wherein the inhibitory nucleic acid comprises a nucleotide sequence designated as "NRC-0119".
11. A method according to any one of claims 1 to 10, wherein the miR-128 inhibitor is formulated for subcutaneous delivery.
12. A method according to any one of claims 1 to 11, wherein the miR-128 inhibitor is formulated as a pharmaceutical composition comprising one or more of pharmaceutically acceptable excipients, buffers, solvents, extenders, flavoring agents, lubricants, coloring agents, binders, surfactants, binders, and disintegrants.
13. A method according to any one of claims 1 to 11, wherein the miR-128 inhibitor is formulated as a pharmaceutical composition comprising a pharmaceutically acceptable excipient.
14. A method according to claim 13, wherein the pharmaceutically acceptable excipient is selected from poly(amidoamine), poly(propyleneimine), and poly(L-lysine).
15. In paragraph 13, the method wherein the above-mentioned pharmaceutically acceptable excipient comprises one or more lipids.
16. A method comprising, in any one of claims 1 to 15, further comprising the step of administering at least one additional therapeutic agent.
17. A method according to claim 16, wherein at least one additional therapeutic agent is selected from testosterone, growth hormone, insulin-like growth factor, mechanical growth factor, urocortin II, anabolic steroid, omega-3 fatty acid, creatine, and dehydroepiandrosterone.
18. A method according to any one of claims 1 to 17, further comprising the step of instructing the individual to perform weight training exercises or resistance training exercises.
19. As a combination therapy for the treatment of age-related sarcopenia, miR-128 inhibitors; and Combination therapy comprising one or more of testosterone, growth hormone, insulin-like growth factor, mechanical growth factor, urocortin II, anabolic steroids, omega-3 fatty acids, creatine, and dehydroepiandrosterone.
20. In paragraph 19, a combination therapy in which the miR-128 inhibitor comprises an inhibitory nucleic acid.

Description

Composition and method for treating sarcopenia Cross-reference of related applications This application claims the benefit of U.S. provisional application No. 63/537,152 filed on September 7, 2023, the full text of which is incorporated herein by reference. Integration by referencing sequence lists provided as XNL files A sequence list is provided with this specification as a sequence list XML, "BERK-489WO_SEQLIST," created on September 6, 2024, with a size of 11,111 bytes. The contents of the sequence list XML are incorporated herein by reference in their entirety. Sarcopenia is defined as the progressive loss of muscle mass and function associated with aging. This loss of muscle mass and function is associated with an increase in adverse outcomes. Frailty and reduced mobility lead to falls, obesity, and impaired ability to recover from disease, ultimately resulting in increased mortality. Currently, there are no approved drugs for the treatment of sarcopenia. The present disclosure provides a composition and a method for treating sarcopenia, including age-related sarcopenia. Various embodiments include an inhibitory nucleic acid, a composition comprising an inhibitory nucleic acid, and a method for treating such disorders using an inhibitory nucleic acid. Figures 1a and 1b provide the nucleotide sequence of an exemplary antisense oligonucleotide (ASO) (Figure 1a; sequence number: 1-3, respectively) and the base pairing site of the ASO within a target microRNA (miR-128-3p) (Figure 1b; sequence number: 12). Figures 2a to 2i show intermediate data illustrating the effects of miR-128-3p-targeted LNA ASO on skeletal muscle function in aged mice. Figures 3a to 3i show the overall experimental data illustrating the effects of miR-128-3p-targeted LNA ASO on skeletal muscle function in aged mice. Figures 4a to 4d experimental data showing the effect of miR-128-3p targeted LNA ASO on skeletal muscle mass in aged mice. definition As used herein, "antisense oligonucleotide" refers to a nucleic acid sequence complementary to a DNA or RNA sequence, such as microRNA. "RNA" refers to a molecule containing at least one ribonucleotide residue. "Ribonucleotide" is a nucleotide having a hydroxyl group at the 2' position of a beta-D-ribofuranose moiety. As used herein, the term RNA includes double-stranded RNA, single-stranded RNA, isolated RNA, e.g., partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as RNA that differs from naturally occurring RNA by the addition, deletion, substitution, and/or alteration of one or more nucleotides. The nucleotides of an RNA molecule may also include non-naturally occurring nucleotides or non-standard nucleotides such as chemically synthesized nucleotides or deoxynucleotides. MicroRNA (miRNA) is a single-stranded RNA molecule approximately 21 to 23 nt in length. Generally, miRNA regulates gene expression. miRNA is encoded by a gene and transcribed from the corresponding DNA, but miRNA is not translated into a protein. Each primary miRNA transcript is processed into a short-stem loop structure before being further processed into functional miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, and their primary function is to downregulate gene expression. As used herein, "interfering RNA" refers to any double-stranded or single-stranded RNA sequence capable of repressing or downregulating gene expression directly or indirectly (i.e., upon conversion) by mediating RNA interference. Interfering RNA includes, but is not limited to, small interfering RNA (“siRNA”) and small hairpin RNA (“shRNA”). "RNA interference" refers to the selective degradation of sequence-compatible messenger RNA transcripts. As used herein, "shRNA (small hairpin RNA) refers to an RNA molecule comprising an antisense region, a loop portion, and a sense region, wherein the sense region has a complementary nucleotide that forms a base pair with the antisense region to form a dimeric stem. After post-transcriptional processing, small hairpin RNA is converted into small interfering RNA by a cleavage event mediated by the enzyme Dicer, a member of the RNase III family. As used herein, “small interfering RNA” or “siRNA” refers to any small RNA molecule capable of suppressing or downregulating gene expression by mediating RNA interference in a sequence-specific manner. Small RNA may be, for example, about 18 to 21 nucleotides long. As used herein, "antagomir" refers to a small synthetic RNA that is complementary to a specific microRNA target and has one or more base modifications to inhibit mispairing or cleavage at the cleavage site. As used herein, the phrase "post-transcriptional processing" refers to mRNA processing that occurs after transcription and is mediated, for example, by the enzymes Dicer and/or Drosha. "Effective dose" refers to the amount of a preparation (e.g., inhibitory nucleic acid of this disclosure) or a compositi