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WO-2026096929-A1 - PERILIPIN 1 (PLIN1)-MODULATING COMPOSITIONS AND METHODS OF USE THEREOF

WO2026096929A1WO 2026096929 A1WO2026096929 A1WO 2026096929A1WO-2026096929-A1

Abstract

Aspects of the disclosure provide compounds, compositions, and methods for modulating the expression or activity of Perilipin 1 (PLIN1). In certain aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of PLIN 1 mRNA in a cell or animal. In certain aspects, the compounds, compositions, and methods of the disclosure can be used to reduce the expression of PLIN 1 protein in a cell or animal.

Inventors

  • LI, ZHEN
  • ZHU, Rui
  • SHEN, Wen

Assignees

  • ADARX PHARMACEUTICALS, INC.

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (20)

  1. 1. A compound comprising a modified oligonucleotide 8 to 30 linked nucleosides in length having a nucleobase sequence comprising at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence of one or more of SEQ ID NOs: 1 or 2.
  2. 2. The compound of claim 1, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 34-53.
  3. 3. The compound of claim 1 or 2, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 34, 35, and 39.
  4. 4. A compound comprising a modified oligonucleotide 8 to 30 linked nucleosides in length having a nucleobase sequence comprising at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence that is fully complementary to an equal length portion of one or more of SEQ ID NOs: 1 or 2.
  5. 5. The compound of claim 4, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-33.
  6. 6. The compound of claim 4 or 5, wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11, 12, and 16.
  7. 7. The compound of any one of claims 1-6, wherein the modified oligonucleotide is 14 to 23 linked nucleosides in length.
  8. 8. The compound of any one of claims 1-7, wherein the modified oligonucleotide comprises a conjugate group. 88 #14556606vl
  9. 9. The compound of claim 8, wherein the conjugate group comprises a targeting moiety.
  10. 10. The compound of claim 9, wherein the targeting moiety is attached to one or more internal positions in the modified oligonucleotide.
  11. 11. The compound of claim 9 or 10, wherein the targeting moiety is attached to the 5’ end and/or the 3’ end of the modified oligonucleotide.
  12. 12. The compound of any one of claims 9-11, wherein the targeting moiety comprises one or more ligands selected from the group consisting of a Tropomyosin receptor B (TrkB) ligand, a cannabinoid receptor type 1 (CBi) ligand, a.4 1/7 integrin ligand, an iV-methyl-D- aspartate receptor (NMD A) ligand, a glutamate transporter- 1 (GLT-1) ligand, and an N- acetyl-galactosamine (GalNAc) moiety.
  13. 13. The compound of any one of claims 9-12, wherein the targeting moiety promotes localization of the compound to a target cell or tissue relative to a non-target cell or tissue.
  14. 14 The compound of claim 13, wherein the target cell or tissue is an adipocyte or adipose tissue, optionally wherein the targeting moiety is a ligand for a receptor selectively expressed on adipocytes.
  15. 15. The compound of any one of claims 8-14, wherein the conjugate group comprises a lipid.
  16. 16. The compound of claim 15, wherein the lipid is attached to an internucleoside linkage of the modified oligonucleotide.
  17. 17. The compound of claim 15 or 16, wherein the lipid comprises a substituted or unsubstituted alkyl or alkenyl.
  18. 18. The compound of claim 17, wherein the substituted or unsubstituted alkyl or alkenyl comprises a saturated or unsaturated Cs-C o hydrocarbon chain. 89 #14556606vl
  19. 19. The compound of any one of claims 1-18, wherein the modified oligonucleotide comprises at least one modification selected from the group consisting of a modified nucleobase, a modified intemucleoside linkage, and a modified sugar.
  20. 20. A compound comprising: a sense strand comprising at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence of one or more of SEQ ID NOs: 1 or 2; and an antisense strand forming a double-stranded region with the sense strand, wherein the compound comprises at least one modification selected from the group consisting of a modified nucleobase, a modified internucleoside linkage, and a modified sugar.

Description

PERILIPIN 1 (PLINl)-MODULATING COMPOSITIONS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/715,296, filed November 1, 2024. The disclosure of the prior application is considered part of and is incorporated by reference in its entirety in the disclosure of this application. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (A127870037WO00-SEQ-JIB.xml; Size 45,427 bytes; and Date of Creation: October 30, 2025) is incorporated herein by reference in its entirety. BACKGROUND [0003] Excessive abdominal obesity, along with other risk factors, is associated with metabolic syndrome, which can lead to heart disease, Type-2 diabetes, and death. Perilipin 1 (PLIN1) is a lipid droplet coating protein known to regulate lipid metabolism in adipocytes, in which it is primarily expressed. PLIN1 is thought to act dually to both suppress basal lipolysis and augment stimulated lipolysis (e.g., when phosphorylated by protein kinase A). Loss of PLIN 1 function in mice results in lean and healthy mice that are resistant to diet- induced obesity, insulin resistance and many related metabolic abnormalities. Similarly, abnormal (e.g., reduced) PLIN1 function in humans results in reduced fat mass, among other potential phenotypes. [0004] Accordingly, there is a need for agents that modulate the expression or activity of PLIN1, and that selectively localize to the specifically desired cell type, organ, or tissue compartment. SUMMARY [0005] The present disclosure provides compounds, compositions, and methods for modulating the expression or activity of perilipin 1 (hereinafter, “PLIN1”). In certain embodiments, the compounds, compositions, and methods can be used to reduce the expression of PLIN1 mRNA in a cell or animal. In certain embodiments, the compounds, 1 #14556606vl compositions, and methods can be used to reduce the amount of PLIN 1 protein in a cell or animal. [0006] In certain embodiments, the animal has or is at risk of having a metabolic syndrome related disease, disorder or condition or a symptom thereof. In certain embodiments, the syndrome, disease, disorder, or condition is associated with PLIN1. In certain embodiments the syndrome, disease, disorder, or condition is metabolic syndrome, obesity, cardiovascular disease (e.g., high blood pressure, high cholesterol, high blood sugar, coronary artery disease, congestive heart failure, heart attack, and stroke), diabetes mellitus (e.g., Type-2 diabetes), insulin resistance, fatty liver disease, kidney disease, energy homeostasis, immune/inflammatory conditions, nausea, diarrhea, fibrogenesis, alcoholic steatohepatitis and diabetic nephropathy. [0007] Certain aspects provide a compound comprising a modified oligonucleotide 8 to 30 (e.g., 8 to 23, 14 to 23, 13 to 20) linked nucleosides in length having a nucleobase sequence comprising at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence of one or more of SEQ ID NOs: 1 or 2. In certain embodiments, the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 34-53. In certain embodiments, the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 34, 35, and 39. [0008] Certain aspects provide a compound comprising a modified oligonucleotide 8 to 30 (e.g., 8 to 23, 14 to 23, 13 to 20) linked nucleosides in length having a nucleobase sequence comprising at least 8 contiguous nucleobases differing by no more than 3 nucleobases from a nucleobase sequence that is fully complementary to an equal length portion of one or more of SEQ ID NOs: 1 or 2. In certain embodiments, the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11-33. In certain embodiments, the nucleobase sequence of the modified oligonucleotide comprises at least 8 contiguous nucleobases of a nucleobase sequence of any one of SEQ ID NOs: 11, 12, and 16. [0009] In certain embodiments, a modified oligonucleotide described herein comprises a conjugate group. In certain embodiments, the conjugate group comprises a targeting moiety. In certain embodiments, the conjugate group comprises a ligand (e.g., a receptor ligand). In certain embodiments, the conjugate group comprises a lipid. In certain embodiments, the conjugate group comprises polyethylene glycol. In certain embodiments, the modified oligonucleotide comprises one or more ligands and one or more lipids. In certain embodiments, the modified oligonucleotide comprises one or more ligands and polyethylene 2 #14556606vl glycol. In certain embodiments, the modified oligonucleotide comprises one or more lipids a