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CN-121991949-A - Double-stranded ribonucleic acid for inhibiting GPR146 gene expression, conjugate and application

CN121991949ACN 121991949 ACN121991949 ACN 121991949ACN-121991949-A

Abstract

The present disclosure relates to double-stranded ribonucleic acids, conjugates, and uses that inhibit GPR146 gene expression. The double-stranded ribonucleic acid provided by the disclosure can be combined in cells to form an RNA-induced silencing complex (RISC), and cut mRNA transcribed by a GPR146 gene, so that the GPR146 gene expression can be selectively and efficiently inhibited, and the double-stranded ribonucleic acid can be used for treating diseases mediated by the GPR146 gene and has important application prospects in clinical disease treatment.

Inventors

  • WANG XIAOJUN
  • LIN GUOLIANG
  • HUANG HE
  • WANG YAN
  • WANG SHUCHENG
  • NIU LIJIAO
  • CHAN YUNXIA
  • GENG YUXIAN

Assignees

  • 北京福元医药股份有限公司

Dates

Publication Date
20260508
Application Date
20251104
Priority Date
20241105

Claims (20)

  1. 1. A double-stranded ribonucleic acid that inhibits expression of the GPR146 gene, comprising a sense strand and an antisense strand, wherein each nucleotide in the double-stranded ribonucleic acid is independently a modified or unmodified nucleotide, the sense strand comprising nucleotide sequence I and the antisense strand comprising nucleotide sequence II, the nucleotide sequence I and the nucleotide sequence II being at least partially reverse complementary to form a double-stranded region, wherein the nucleotide sequence I and the nucleotide sequence II are selected from the group consisting of: (1) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 1, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 2: 5'- GGUCCUCACCAGAGCUCUA -3' (SEQ ID NO: 1) 5'- UAGAGCUCUGGUGAGGACC -3' (SEQ ID NO: 2); (2) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 3, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 4: 5'- CAGAUCCCCUUCAAUGUGU -3' (SEQ ID NO: 3) 5'- ACACAUUGAAGGGGAUCUG -3' (SEQ ID NO: 4); (3) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 7, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 8: 5'- CUCCCAAACACGCAGCUCA -3' (SEQ ID NO: 7) 5'- UGAGCUGCGUGUUUGGGAG -3' (SEQ ID NO: 8); (4) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 9, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 10: 5'- GAGCCAGUAUUUAUACUUU -3' (SEQ ID NO: 9) 5'- AAAGUAUAAAUACUGGCUC -3' (SEQ ID NO: 10); (5) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 11, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 12: 5'- ACAGAUGUUUCCUAGAAAA -3' (SEQ ID NO: 11) 5'- UUUUCUAGGAAACAUCUGU -3' (SEQ ID NO: 12); (6) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 13, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 14: 5'- GAGGUUUUUUUCAGUAUGA -3' (SEQ ID NO: 13) 5'- UCAUACUGAAAAAAACCUC -3' (SEQ ID NO: 14); (7) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 15, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 16: 5'- GUCCUAAAUCAAUUCCUCA -3' (SEQ ID NO: 15) 5'- UGAGGAAUUGAUUUAGGAC -3' (SEQ ID NO: 16); (8) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 17, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 18: 5'- GCAUUCAGUUUGUCAAU -3' (SEQ ID NO: 17) 5'- AUUGACAAACUGAAUGC -3' (SEQ ID NO: 18); (9) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 19, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 20: 5'- GGUUAAAAUA -3' (SEQ ID NO: 19) 5'- UAUUUUAACC -3' (SEQ ID NO: 20); (10) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 21, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 22: 5'- CCCCUUGUUUGUUU -3' (SEQ ID NO: 21) 5'- AAACAAACAAGGGG -3' (SEQ ID NO: 22); (11) The nucleotide sequence I comprises a nucleotide sequence shown as SEQ ID NO. 23, and the nucleotide sequence II comprises a nucleotide sequence shown as SEQ ID NO. 24: 5'- CACAAAACUAAA -3' (SEQ ID NO: 23) 5'- UUUAGUUUUGUG -3' (SEQ ID NO: 24)。
  2. 2. The double-stranded ribonucleic acid according to claim 1, wherein said sense strand further comprises a nucleotide sequence III and said antisense strand further comprises a nucleotide sequence IV, each independently 0-9 nucleotides in length, wherein said nucleotide sequence III is attached to the 5' -end of said nucleotide sequence I and said nucleotide sequence IV is attached to the 3' -end of said nucleotide sequence II, said nucleotide sequence III and said nucleotide sequence IV are of equal length and are essentially complementary in reverse or are complementary in reverse in nature, wherein said essentially complementary in reverse is that there is no more than 1 base mismatch between the two nucleotide sequences, wherein said complementary in reverse is that there is no mismatch between the two nucleotide sequences, and/or wherein said nucleotide sequence IV is attached to the 3' -end of said nucleotide sequence II The nucleotide sequence III is connected to the 3 '-end of the nucleotide sequence I, the nucleotide sequence IV is connected to the 5' -end of the nucleotide sequence II, the nucleotide sequence III and the nucleotide sequence IV are equal in length and are substantially reverse complementary or completely reverse complementary, wherein the substantial reverse complementary means that no more than 1 base mismatch exists between the two nucleotide sequences, and the completely reverse complementary means that no mismatch exists between the two nucleotide sequences.
  3. 3. The double-stranded ribonucleic acid according to claim 1 or 2, wherein said sense strand further comprises a nucleotide sequence V and/or said antisense strand further comprises a nucleotide sequence VI, each independently 0-2 nucleotides in length, said nucleotide sequence V being linked at the 3 'end of said sense strand to form a 3' overhang of the sense strand and/or said nucleotide sequence VI being linked at the 3 'end of said antisense strand to form a 3' overhang of the antisense strand, preferably said nucleotide sequence V or said nucleotide sequence VI each being 2 nucleotides in length, more preferably said nucleotide sequence V or said nucleotide sequence VI is UU, AU, UA, AG, AA, AC, CU or CA in the direction of the 5 'end towards the 3' end; Or the nucleotide sequence V is identical to or has a nucleotide difference from the nucleotide at the corresponding position of the target mRNA, or the nucleotide sequence VI is mismatched or complementary to the nucleotide at the corresponding position of the target mRNA.
  4. 4. The double-stranded ribonucleic acid of any one of claims 1 to 3, comprising a sense strand and an antisense strand, said sense strand and said antisense strand being selected from the following sequences: The sense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 33 and the antisense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 57; The sense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 47 and the antisense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 58, or The sense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 55 and the antisense strand comprises or consists of the nucleotide sequence shown as SEQ ID NO. 59.
  5. 5. The double-stranded ribonucleic acid according to any one of claims 1 to 4, wherein the length of the double-stranded region is 10 to 30 nucleotide pairs, preferably 17 to 25 nucleotide pairs, more preferably 19 to 23 nucleotide pairs, further preferably 19, 20, 21, 22 or 23 nucleotide pairs, and/or The sense strand or the antisense strand has 15 to 30 nucleotides, preferably 17 to 25 nucleotides, more preferably 19 to 23 nucleotides, further preferably 19, 20, 21, 22 or 23 nucleotides.
  6. 6. The double-stranded ribonucleic acid of any one of claims 1 to 5, wherein each nucleotide in the sense strand is a modified nucleotide or an unmodified nucleotide independently of each other and/or each nucleotide in the antisense strand is a modified nucleotide or an unmodified nucleotide independently of each other; Preferably, the modified nucleotide is selected from the group consisting of 2 '-fluoro modified nucleotide, 2' -alkoxy modified nucleotide, 2 '-substituted alkoxy modified nucleotide, 2' -alkyl modified nucleotide, 2 '-substituted alkyl modified nucleotide, 2' -deoxy modified nucleotide, 2 '-amino modified nucleotide, 2' -substituted amino modified nucleotide, nucleotide analogue or a combination of any two or more thereof; More preferably, the modified nucleotide is selected from the group consisting of a2 '-fluoro modified nucleotide, a 2' -methoxy modified nucleotide, a 2'-O-CH 2 -CH 2 -O-CH 3 modified nucleotide, a 2' -O-CH 2 -CH=CH 2 modified nucleotide, a 2'-CH 2 -CH 2 -CH=CH 2 modified nucleotide, a 2' -deoxy modified nucleotide, a nucleotide analog, or a combination of any two or more thereof; further preferably, the nucleotide analogue is selected from the group consisting of an iso-nucleotide, LNA, ENA, cET-BNA, UNA or GNA.
  7. 7. The double-stranded ribonucleic acid according to any one of claims 1 to 6, wherein any two nucleotides linked in the sense strand are linked by a phosphodiester bond or a phosphorothioate group, and/or The two nucleotides optionally linked in the antisense strand are linked by a phosphodiester bond or a phosphorothioate group, and/or The 5 'terminal nucleotide of the antisense strand is linked to a 5' phosphate group or a 5 'phosphate derivative group, or the 5' terminal nucleotide of the antisense strand is not linked to a 5 'phosphate group or a 5' phosphate derivative group.
  8. 8. The double stranded ribonucleic acid of any one of claims 1 to 7, wherein the sense strand comprises one or more end capping residues or moieties or the sense strand does not comprise end capping residues or moieties; Preferably, the end capping residue is a reverse abasic deoxyribose residue; further preferably, the 3 'terminal nucleotide and/or the 5' terminal nucleotide of the sense strand is linked to one or more of the reverse abasic deoxyribose residues; more preferably, the 3' -terminal nucleotide of the sense strand is linked to one or more of the reverse abasic deoxyribose residues; more preferably, the inverted abasic deoxyribose residue is linked to the 3 'terminal nucleotide and/or 5' terminal nucleotide of the sense strand by a phosphodiester linkage, phosphorothioate linkage, or other internucleoside linkage.
  9. 9. The double-stranded ribonucleic acid of any one of claims 1 to 8, wherein the double-stranded ribonucleic acid is an siRNA.
  10. 10. The double stranded ribonucleic acid of any one of claims 1 to 9, wherein each nucleotide in the sense strand and the antisense strand is independently a 2' -fluoro modified nucleotide or a non-fluoro modified nucleotide; Preferably, in the sense strand, the 2' -fluoro-modified nucleotide is located at positions 9, 10, 11 and 13, the remaining positions are non-fluoro-modified nucleotides, or the 2' -fluoro-modified nucleotide is located at positions 11, 12, 13 and 15, the remaining positions are non-fluoro-modified nucleotides, or the 2' -fluoro-modified nucleotide is located at positions 11, 12, 13 and 17, the remaining positions are non-fluoro-modified nucleotides, or the 2' -fluoro-modified nucleotide is located at positions 9, 11, 13 and 17, the remaining positions are non-fluoro-modified nucleotides, or the 2' -fluoro-modified nucleotide is located at positions 6, 11 and 13, the remaining positions are non-fluoro-modified nucleotides, and/or In the antisense strand, along the direction from the 5' end to the 3' end, 2' -fluoro modified nucleotides are positioned at positions 2, 6, 14 and 16, the rest positions are non-fluoro modified nucleotides, or 2' -fluoro modified nucleotides are positioned at positions 2, 7, 10 and 14, the rest positions are non-fluoro modified nucleotides, or 2' -fluoro modified nucleotides are positioned at positions 2, 3, 5, 7, 10, 12 and 14, and the rest positions are non-fluoro modified nucleotides.
  11. 11. The double stranded ribonucleic acid of any one of claims 1 to 10, wherein each nucleotide in the sense strand and the antisense strand is independently a2 '-fluoro modified nucleotide, a 2' -methoxy modified nucleotide and/or a GNA modified nucleotide; Preferably, in the sense strand, the 2 '-fluoro modified nucleotide is located at positions 9,10, 11 and 13 with the 2' -methoxy modified nucleotide at the rest positions, or the 2 '-fluoro modified nucleotide is located at positions 11, 12, 13 and 15 with the 2' -methoxy modified nucleotide at the rest positions, or the 2 '-fluoro modified nucleotide is located at positions 11, 12, 13 and 17 with the 2' -methoxy modified nucleotide at the rest positions, or the 2 '-fluoro modified nucleotide is located at positions 9, 11, 13 and 17 with the 2' -methoxy modified nucleotide at the rest positions, or the 2 '-fluoro modified nucleotide is located at positions 6, 11 and 13 with the 2' -methoxy modified nucleotide at the rest positions, and/or In the antisense strand, 2 '-fluoro modified nucleotides are positioned at positions 2, 6, 14 and 16 along the direction from the 5' end to the 3 'end, the rest positions are 2' -methoxy modified nucleotides, or 2 '-fluoro modified nucleotides are positioned at positions 2, 7, 10 and 14, the rest positions are 2' -methoxy modified nucleotides, or 2 '-fluoro modified nucleotides are positioned at positions 2, 3, 5, 7, 10, 12 and 14, GNA modified nucleotides are positioned at position 6 of the antisense strand, and the rest positions are 2' -methoxy modified nucleotides.
  12. 12. The double-stranded ribonucleic acid of any one of claims 1 to 11, said sense strand comprising phosphorothioate groups in the 5 'to 3' direction at positions as shown below: between nucleotide 1 and nucleotide 2 from the 5' end of the sense strand; Between nucleotide 2 and nucleotide 3 from the 5' end of the sense strand; Or alternatively The sense strand comprises phosphorothioate groups at the positions shown below: Between the 1 st nucleotide starting at the 5' end of the sense strand and the reverse abasic deoxyribose residue; between nucleotide 1 and nucleotide 2 from the 5' end of the sense strand; between nucleotide 1 starting at the 3' -end of the sense strand and the reverse abasic deoxyribose residue; Or alternatively The sense strand comprises phosphorothioate groups at the positions shown below: between nucleotide 1 and nucleotide 2 from the 5' end of the sense strand; Between nucleotide 2 and nucleotide 3 from the 5' end of the sense strand; Between the 1 st nucleotide of the 3' -end initiation of the sense strand and the inverted abasic deoxyribose residue.
  13. 13. The double-stranded ribonucleic acid of any one of claims 1 to 12, said antisense strand comprising phosphorothioate groups in the 5 'to 3' direction at positions as shown below: between nucleotide 1 and nucleotide 2 from the 5' end of the antisense strand; between nucleotide 2 and nucleotide 3 from the 5' end of the antisense strand; Between nucleotide 1 and nucleotide 2 from the 3' end of the antisense strand; The antisense strand is between nucleotide 2 and nucleotide 3 from the 3' terminus.
  14. 14. The double-stranded ribonucleic acid of any one of claims 1 to 13, wherein the 2 '-fluoro modified nucleotide is located at positions 9, 10, 11 and 13 of the sense strand in the direction of the 3' terminus towards the 5 'terminus and the remaining positions are 2' -methoxy modified nucleotides, the 2 '-fluoro modified nucleotide is located at positions 2, 6, 14 and 16 of the antisense strand in the direction of the 5' terminus towards the 3 'terminus and the remaining positions are 2' -methoxy modified nucleotides, the 5 '-terminal nucleotide of the antisense strand being linked to a 5' phosphate group; Or in the direction of the 3' end towards the 5' end, the 2' -fluoro modified nucleotide is positioned at positions 9, 10, 11 and 13 of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5' end towards the 3' end, the 2' -fluoro modified nucleotide is positioned at positions 2, 6, 14 and 16 of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, the 5' end nucleotide of the antisense strand is not connected with a 5' phosphate group or a 5' phosphate derivative group; Or in the direction of the 3 'end towards the 5' end, the 2 '-fluoro modified nucleotide is positioned at positions 9, 10, 11 and 13 of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5 'end towards the 3' end, the 2 '-fluoro modified nucleotide is positioned at positions 2, 6, 14 and 16 of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, the 5 '-end nucleotide of the antisense strand is connected with a 5' -trans vinyl phosphonate group; Or in the direction of the 3' end towards the 5' end, the 2' -fluoro modified nucleotide is positioned at the 11 th, 12 th, 13 th and 15 th positions of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5' end towards the 3' end, the 2' -fluoro modified nucleotide is positioned at the 2 nd, 6 th, 14 th and 16 th positions of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, the 5' end nucleotide of the antisense strand is not connected with a 5' phosphate group or a 5' phosphate derivative group; Or in the direction of the 3 'end towards the 5' end, the 2 '-fluoro modified nucleotide is positioned at the 11 th, 12 th, 13 th and 15 th positions of the sense strand, and the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5 'end towards the 3' end, the 2 '-fluoro modified nucleotide is positioned at the 2 nd, 6 th, 14 th and 16 th positions of the antisense strand, and the rest positions are 2' -methoxy modified nucleotides, wherein the 5 '-end nucleotide of the antisense strand is connected with a 5' -trans vinyl phosphonate group; Or in the direction of the 3 'end towards the 5' end, the 2 '-fluoro modified nucleotide is positioned at the 11 th, 12 th, 13 th and 17 th positions of the sense strand, and the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5 'end towards the 3' end, the 2 '-fluoro modified nucleotide is positioned at the 2 nd, 7 th, 10 th and 14 th positions of the antisense strand, and the rest positions are 2' -methoxy modified nucleotides, wherein the 5 '-end nucleotide of the antisense strand is connected with a 5' -trans vinyl phosphonate group; or in the direction of the 3 'end towards the 5' end, the 2 '-fluoro modified nucleotide is positioned at positions 9, 11, 13 and 17 of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction of the 5 'end towards the 3' end, the 2 '-fluoro modified nucleotide is positioned at positions 2, 7, 10 and 14 of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, the 5 '-end nucleotide of the antisense strand is connected with a 5' -trans vinyl phosphonate group; or in the direction from the 3 'end to the 5' end, 2 '-fluoro modified nucleotides are positioned at positions 6, 11 and 13 of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction from the 5 'end to the 3' end, 2 '-fluoro modified nucleotides are positioned at positions 2, 7, 10 and 14 of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, the 5 '-end nucleotides of the antisense strand are connected with 5' -trans vinyl phosphonate groups; Or in the direction from the 3 'end to the 5' end, 2 '-fluoro modified nucleotides are positioned at positions 9, 11, 13 and 17 of the sense strand, the rest positions are 2' -methoxy modified nucleotides, in the direction from the 5 'end to the 3' end, 2 '-fluoro modified nucleotides are positioned at positions 2, 3, 5, 7, 10, 12 and 14 of the antisense strand, GNA modified nucleotides are positioned at position 6 of the antisense strand, the rest positions are 2' -methoxy modified nucleotides, and the 5 '-end nucleotides of the antisense strand are connected with a 5' -trans vinyl phosphonate group.
  15. 15. The double stranded ribonucleic acid of any one of claims 1 to 14, wherein the sense strand and the antisense strand are selected from the group consisting of: the sense strand comprises the sense strand of any one of the siRNAs set forth in tables 1, 1-1 and 1-2 herein, and the antisense strand comprises the antisense strand of the corresponding siRNA; Preferably, the siRNA is selected from the group consisting of N-ER-FY033131、N-ER-FY033131M44、N-ER-FY033131M48、N-ER-FY033131M49、N-ER-FY033131M50、N-ER-FY033147、N-ER-FY033147M44、N-ER-FY033147M49、N-ER-FY033147M50、N-ER-FY033151、N-ER-FY033151M44、N-ER-FY033151M49、N-ER-FY033151M50.
  16. 16. A double-stranded ribonucleic acid conjugate, or a prodrug thereof, wherein the double-stranded ribonucleic acid conjugate comprises the double-stranded ribonucleic acid of any one of claims 1-15, and a conjugate group conjugated to the double-stranded ribonucleic acid.
  17. 17. The double stranded ribonucleic acid conjugate of claim 16, or a prodrug thereof, wherein the conjugate group is attached to the 3' end of the sense strand; Preferably, the conjugate group is conjugated to the 3 'end of the sense strand via a phosphodiester linkage, or the conjugate group is conjugated to an inverted abasic deoxyribose residue at the 3' end of the sense strand via a phosphorothioate group.
  18. 18. The double-stranded ribonucleic acid conjugate of claim 16 or 17, or a prodrug thereof, wherein said conjugate group is selected from any one of the group consisting of formulas (I) to (VIII): Formula (I) Formula (II) Formula (III) (IV) (V) (VI) (VII) Formula (VIII).
  19. 19. The double-stranded ribonucleic acid conjugate of any one of claims 16 to 18, or a prodrug thereof, wherein the double-stranded ribonucleic acid conjugate has a structure as shown in formula (IX): Formula (IX), Wherein the double-helix structure is double-stranded ribonucleic acid.
  20. 20. The double stranded ribonucleic acid conjugate of any one of claims 16 to 19, or a prodrug thereof, wherein the double stranded ribonucleic acid conjugate is an siRNA conjugate.

Description

Double-stranded ribonucleic acid for inhibiting GPR146 gene expression, conjugate and application Technical Field The present disclosure is in the field of biological medicine, and in particular, relates to a double-stranded ribonucleic acid, a double-stranded ribonucleic acid conjugate, or a prodrug, a pharmaceutical composition and use thereof for inhibiting GPR146 gene expression, and a method for inhibiting GPR146 gene expression in a cell in vivo or in vitro. Background G protein-coupled receptor 146 (GPR 146) induces hepatic sterol regulatory element binding protein 2 (SREBP 2) by activating extracellular signal regulated kinase 1/2 (ERK 1/2) signaling, resulting in secretion of Very Low Density Lipoprotein (VLDL) by the liver. The lack of mouse GPR146 has been shown to reduce hepatic secretion of Low Density Lipoprotein (LDL) precursor VLDL and prevent diet-induced atherosclerosis in LDL receptor knockout mice. Studies have shown that GPR146 may be associated with the occurrence of Atherosclerosis (AS) and familial hypercholesterolemia (HoFH). AS is still a major cause of coronary artery disease, cerebral infarction and peripheral vascular disease, and places a burden on the public worldwide. Lipids were found to be the major deposit under the aortic intima, involved in the formation of atherosclerotic plaques, leading to AS. At the same time, plasma lipid and lipoprotein disorders, such AS elevated plasma low density lipoprotein cholesterol (LDL-C) and Triglycerides (TGs), are the major pathological basis for AS progression. It is also notable that HoFH is a common inherited metabolic disorder characterized by severe elevated low-density lipoprotein cholesterol levels, leading to early cardiovascular disease morbidity and mortality. Studies have shown that over 95% of HoFH patients exhibit loss-of-function mutations in both Low Density Lipoprotein Receptor (LDLR) alleles. Thus, inhibition of GPR146 may be an effective strategy for modulating cholesterol levels for AS and HoFH treatment. At the same time, the identification of new therapeutic targets for LDL lowering drugs independent of LDLR activity in HoFH is urgent and of great importance （Lan She et al. GPR146: an emerging therapeutic target for hypercholesterolemia and atherosclerosis. Acta Biochim Biophys Sin (Shanghai). 2020 Aug 5;52(8)914-915.;Antoine Rimbert et al., Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile. Arteriosclerosis, Thrombosis, and Vascular Biology. Volume42,Number10）. In addition, nonspecific orbital inflammation (NSOI) is a chronic idiopathic disease characterized by extensive polymorphic lymphoid infiltration of the orbital region. Zixuan Wu et al analyzed the correlation between GPR146 gene expression and immune cell infiltration, thereby elucidating the immunological features of GPR146 in the context of NSOI, resulting in a therapeutic strategy for GPR146 against the immune metabolic pathway in NSOI （Zixuan Wu et al., Elucidating the multifaceted roles of GPR146 in non-specific orbital inflammation a concerted analytical approach through the prisms of bioinformatics and machine learning, Front Med (Lausanne). 2024 Jun 5:11:1309510.）. Taken together, nonspecific orbital inflammation, hypercholesterolemia, atherosclerosis and coronary artery disease can be prevented and/or treated by inhibiting GPR146 gene expression. Therefore, the development of drugs targeting the GPR146 target has important value. Disclosure of Invention Problems to be solved by the invention In view of the problems in the prior art, for example, there is a need to develop inhibitors of GPR146 for the prevention and/or treatment of GPR 146-related diseases including non-specific orbital inflammation, hypercholesterolemia, atherosclerosis and coronary artery disease, among others, as well as other unidentified related disorders, pathologies or syndromes. The present disclosure aims to provide a series of double-stranded ribonucleic acids, double-stranded ribonucleic acid conjugates or prodrugs thereof for inhibiting GPR146 gene expression, and pharmaceutical compositions, which can be effectively applied to RNA-induced silencing complex (RISC) -mediated cleavage of RNA transcripts of GPR146 gene, thereby being capable of selectively and effectively inhibiting GPR146 gene expression, and having important application prospects in clinical disease treatment. Solution for solving the problem In a first aspect, the present disclosure provides a double-stranded ribonucleic acid that inhibits expression of the GPR146 gene, comprising a sense strand and an antisense strand, wherein each nucleotide in the double-stranded ribonucleic acid is independently a modified or unmodified nucleotide, the sense strand comprising nucleotide sequence I, and the antisense strand comprising nucleotide sequence II, the nucleotide sequence I and the nucleotide sequence II being at least partially reverse complementary to form a double-st