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CN-121986168-A - Inhibitors of expression and/or function

CN121986168ACN 121986168 ACN121986168 ACN 121986168ACN-121986168-A

Abstract

The present application relates to inhibitors, compositions comprising inhibitors and their use in the treatment or prevention of metabolic diseases or disorders, such as metabolic diseases or disorders associated with non-alcoholic fatty liver disease (NAFLD), and/or obesity, and/or diseases or disorders associated with adipogenesis.

Inventors

  • A. V. Whitmore
  • S. Malandraki Miller
  • I. Desantiyago
  • N. Purcell
  • G. S. Gianniotas

Assignees

  • 唐格拉姆治疗公司

Dates

Publication Date
20260505
Application Date
20240206
Priority Date
20230206

Claims (20)

  1. 1. An inhibitor of expression and/or function of SLC25A5/ANT2, wherein the inhibitor is conjugated to one or more ligand moieties, preferably wherein the ligand moieties allow targeting to hepatocytes.
  2. 2. The inhibitor of claim 1, wherein the inhibitor is an siRNA oligomer.
  3. 3. An inhibitor of expression and/or function of SLC25A5/ANT2, wherein the inhibitor is an siRNA oligomer.
  4. 4. The inhibitor of claim 3, wherein the inhibitor comprises an siRNA oligomer conjugated to one or more ligand moieties, preferably wherein the ligand moieties allow for targeting hepatocytes.
  5. 5. The inhibitor of claim 1,2 or 4, wherein the one or more ligand moieties comprise one or more GalNAc ligands or comprise one or more GalNAc ligand derivatives.
  6. 6. The inhibitor of claim 1, 2 or 4, wherein the one or more ligand moieties comprise one or more GalNAc ligand derivatives.
  7. 7. The inhibitor of any one or more of the preceding claims, wherein the inhibitor targets SLC25A5/ANT2.
  8. 8. The inhibitor of any one or more of the preceding claims, wherein the inhibitor is a nucleic acid for inhibiting expression of SLC25A5, the nucleic acid comprising a duplex region comprising a first strand and a second strand at least partially complementary to the first strand, wherein (I) At least partially complementary to a portion of RNA transcribed from the SLC25A5 gene, and (Ii) Comprising at least 17 consecutive nucleosides that differ from any of the first strand sequences listed in table 2 by 0 or 1 nucleoside.
  9. 9. The inhibitor of any one or more of the preceding claims, wherein the inhibitor is a nucleic acid for inhibiting expression of SLC25A5, the nucleic acid comprising a duplex region comprising a first strand and a second strand at least partially complementary to the first strand, wherein the first strand: (i) At least partially complementary to a portion of RNA transcribed from the SLC25A5 gene, and (Ii) Comprising at least 17 consecutive nucleosides that differ from any of the first strand modification sequences listed in table 3 by 0 or 1 nucleoside.
  10. 10. The inhibitor according to claim 8 or 9, wherein the first strand comprises nucleosides 2-18 of any of the sequences defined in claim 8 or 9, in particular wherein the first strand comprises nucleosides 2-18 of any of the sequences defined in table 2 or 3.
  11. 11. The inhibitor of claim 8, wherein the second strand comprises a nucleotide sequence of at least 17 consecutive nucleosides that differ from any of the second strand sequences listed in table 2 by 0 or 1 nucleoside, and wherein the second strand has a region of at least 85% complementarity over 17 consecutive nucleosides with the first strand.
  12. 12. The inhibitor of claim 9, wherein the second strand comprises a nucleotide sequence of at least 17 consecutive nucleosides that differ by 0 or 1 nucleoside from any of the second strand modification sequences listed in table 4, and wherein the second strand has a region of at least 85% complementarity on 17 consecutive nucleosides with the first strand.
  13. 13. The inhibitor of claim 8, wherein the first strand comprises any of the first strand sequences listed in table 2.
  14. 14. The inhibitor of claim 9, wherein the first strand comprises any of the first strand modification sequences listed in table 3.
  15. 15. The inhibitor of claim 11, wherein the second strand comprises any of the second strand sequences listed in table 2.
  16. 16. The inhibitor of claim 12, wherein the second strand comprises any of the first strand modification sequences listed in table 4.
  17. 17. The inhibitor according to claim 13, wherein said first strand comprises any of the sequences SEQ ID NO. 304, SEQ ID NO. 323, SEQ ID NO. 439, SEQ ID NO. 453 and SEQ ID NO. 496.
  18. 18. The inhibitor according to claim 14, wherein the first strand comprises any of SEQ ID NO 856, SEQ ID NO 875, SEQ ID NO 991, SEQ ID NO 1005 and SEQ ID NO 1048.
  19. 19. The inhibitor according to claim 15, wherein the second strand comprises any one of SEQ ID No. 580, SEQ ID No. 599, SEQ ID No. 715, SEQ ID No. 729 and SEQ ID No. 772.
  20. 20. The inhibitor of claim 16, wherein the second strand comprises any of SEQ ID No. 1132, SEQ ID No. 1151, SEQ ID No. 1267, SEQ ID No. 1281, and SEQ ID No. 1324.

Description

Inhibitors of expression and/or function Technical Field The present application provides inhibitors, e.g., nucleic acid compounds, e.g., siRNA, suitable for therapeutic use. In addition, the application provides methods of preparing these compounds, and methods of using such compounds in the treatment of various diseases and conditions. Background Inhibitors, such as oligonucleotide/oligonucleotide compounds that are inhibitors of gene expression and/or inhibitors of expression or function of other targets (e.g., LNCRNA), have medical important therapeutic applications. Oligonucleotides/oligonucleotides can be used to silence genes that cause a particular disease. Gene silencing prevents the formation of proteins by inhibiting translation. Importantly, gene silencing agents are potential alternatives to traditional small organic compounds that inhibit disease-related protein function. siRNA, antisense RNA and microrna are oligonucleotides/oligonucleotides that prevent protein formation by gene silencing. Over the last two decades, a number of modified siRNA compounds have been developed for diagnostic and therapeutic purposes, including siRNA/RNAi therapeutics for the treatment of various diseases (including central nervous system diseases, inflammatory diseases, metabolic disorders, oncology, infectious diseases and ocular diseases). The present application relates to inhibitors (e.g., oligomers, e.g., nucleic acids, e.g., oligonucleotide/oligonucleotide compounds) and their use in the treatment and/or prevention of diseases. The SLC25A5 gene belongs to the ANT gene family, which itself belongs to the superfamily comprising the gene encoding the brown fat mitochondrial uncoupling protein and the gene encoding the mitochondrial phosphate carrier protein. The gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product adenine nucleotide transporter 2 (ANT 2) of this gene is the major component of the mitochondrial permeability transition pore complex, which catalyzes the exchange of mitochondrial ATP with cytoplasmic ADP. Due to its antiport function ANT2 maintains mitochondrial membrane potential by modulating ADP/ATP ratio in oxidative phosphorylation. ANT2 promotes the uncoupling of the mitochondrial membrane when acylated by SIRT 4. Although decoupling membrane potential generally leads to apoptosis, ANT2 was found to have anti-apoptotic effects. Thus, ANT2 is presumed to mediate TFIIH-dependent DNA damage responses as an integral part of MMS 19-XPD. Disclosure of Invention The application is defined in the claims and in particular relates to: In one aspect, the application relates to an inhibitor of the expression and/or function of SLC25A5/ANT2, wherein the inhibitor is conjugated to one or more ligand moieties. In a further aspect, the application relates to an inhibitor according to the application, wherein the inhibitor is an siRNA oligomer. In another aspect, the application relates to an inhibitor of the expression and/or function of SLC25A5/ANT2, wherein the inhibitor is an siRNA oligomer. In a further aspect, the application relates to an inhibitor according to the application, wherein the inhibitor comprises an siRNA oligomer conjugated to one or more ligand moieties. In a further aspect, the application relates to an inhibitor according to the application, wherein the one or more ligand moieties comprise one or more GalNAc ligands or comprise one or more GalNAc ligand derivatives. In a further aspect, the application relates to an inhibitor according to the application, wherein the one or more ligand moieties comprise one or more GalNAc ligand derivatives. In a further aspect, the application relates to an inhibitor according to the application, wherein the target of the inhibitor is SLC25A5/ANT2. In a further aspect, the present application relates to an inhibitor according to the present application, wherein the inhibitor is a nucleic acid for inhibiting the expression of SLC25A5, said nucleic acid comprising a duplex region comprising a first strand and a second strand at least partially complementary to said first strand, wherein (I) At least partially complementary to a portion of RNA transcribed from the SLC25A5 gene, and (Ii) Comprising at least 17 consecutive nucleosides that differ from any of the first strand sequences listed in table 2 by 0 or 1 nucleoside. In a further aspect, the present application relates to an inhibitor of the present application, wherein the inhibitor is a nucleic acid for inhibiting expression of SLC25A5, the nucleic acid comprising a duplex region comprising a first strand and a second strand at least partially complementary to the first strand, wherein the first strand: (i) At least partially complementary to a portion of RNA transcribed from the SLC25A5 gene, and (Ii) Comprising at least 17 consecutive nucleosides that differ from any of the first strand modification sequences listed in table 3 by 0 or 1 nucleoside