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CN-121991956-A - SiRNA for inhibiting XDH gene expression, and modified product and application thereof

CN121991956ACN 121991956 ACN121991956 ACN 121991956ACN-121991956-A

Abstract

The invention belongs to the field of biological medicine, and in particular relates to siRNA for inhibiting XDH gene expression, a modifier and an application thereof, wherein the siRNA comprises a sense strand and an antisense strand, the sense strand and/or the antisense strand has a length ranging from 19 to 25 nucleotides, the antisense strand is reversely complementary with a section on a target gene, the sense strand has a nucleotide sequence shown as SEQ ID NO.8, and the antisense strand has a nucleotide sequence shown as SEQ ID NO. 25. The siRNA molecules and modified siRNA molecules have high stability and/or high inhibitory activity. The ligand conjugated siRNA molecule has high inhibition activity and stability, good liver targeting property and capacity of promoting endocytosis, can reduce the influence on other tissues or organs and the use amount of the siRNA molecule, and can achieve the aims of reducing toxicity and reducing cost.

Inventors

  • ZHANG YU
  • ZHAO CHENGJIANG
  • ZHANG HANXIN
  • FU CHUANJUN
  • Xie Jinen

Assignees

  • 丽珠医药集团股份有限公司

Dates

Publication Date
20260508
Application Date
20240903
Priority Date
20231229

Claims (10)

  1. 1. An siRNA for inhibiting xanthine oxidase gene expression, which is characterized by comprising a sense strand and an antisense strand, wherein the antisense strand is reversely complementary to a segment on a target gene; The sense strand has a nucleotide sequence as shown in SEO ID No.8 and the antisense strand has a nucleotide sequence as shown in SEO ID No. 25.
  2. 2. The siRNA according to claim 1, wherein at least one nucleotide in the siRNA is modified, wherein the modified nucleotide is selected from one or more of a sugar moiety modification at the 2' position, or wherein at least one phosphate group is a phosphate group containing a modifying group, or a nucleotide analog.
  3. 3. The siRNA of claim 4, wherein said 2 'modified nucleotide comprises a 2' -O-methyl, 2 '-O-methoxyethyl (2' -O-MOE), 2 '-O-aminopropyl, 2' -deoxy, T-deoxy-2 '-fluoro, 2' -O-aminopropyl (2 '-O-AP), 2' -O-dimethylaminoethyl (2 '-O-DMAOE), 2' -O-dimethylaminopropyl (2 '-ODMAP), T-O-dimethylaminoethoxyethyl (2' -O-DMAEOE) or 2 '-O-N-methylacetamido (2' -O-NMA) modified nucleotide.
  4. 4. The siRNA of claim 2, wherein the phosphate group containing a modifying group is a phosphorothioate group formed by substitution of at least one oxygen atom of a phosphodiester bond with a sulfur atom.
  5. 5. The siRNA of claim 2, wherein the nucleotide analogue is selected from one of an iso-nucleotide, LNA, ENA, cEt BNA, UNA or GNA.
  6. 6. The siRNA according to any one of claims 2-5, wherein the modified siRNA molecule has a sense strand structure as shown in SEO ID No.46 and the modified siRNA molecule has an antisense strand structure as shown in SEO ID No. 102.
  7. 7. The siRNA of claim 6 wherein the 3' terminus of said sense strand is conjugated to a ligand comprising GalNAc, cholesterol, biotin, a vitamin, a galactose derivative or analog, a lactose derivative or analog, an N-acetylglucosamine derivative or analog.
  8. 8. The siRNA of claim 7, wherein said ligand is L96.
  9. 9. A biomaterial associated with the siRNA according to any one of claims 1 to 8, characterized by any one of the following: 1) A vector comprising the siRNA of any one of claims 1-8; 2) A reagent or kit comprising the siRNA of any one of claims 1-8 or the vector of 1); 3) A pharmaceutical composition consisting of the siRNA molecule of any one of claims 1 to 8 and a pharmaceutically acceptable additional component.
  10. 10. Use of the siRNA of any one of claims 1-8 or the biomaterial of claim 9 for the treatment of hyperuricemia.

Description

SiRNA for inhibiting XDH gene expression, and modified product and application thereof The application relates to a split application of China patent with application date 2024.09.03, application number 202480001800.7 and the application name of siRNA for inhibiting XDH gene expression and modifications and application thereof. Technical Field The invention belongs to the field of biological medicine, and in particular relates to siRNA for inhibiting XDH gene expression, a modified product and application thereof. Background Hyperuricemia refers to uric acid levels in the blood that exceed normal ranges, typically less than 420. Mu. Mol/L in men and less than 360. Mu. Mol/L in women. Elevated uric acid levels are the biochemical basis for hyperuricemia and gout, a chronic metabolic disease caused by deposition of urate crystals on joints and other tissues, manifested by recurrent episodes of acute arthritis, chronic joint deformity, tophus, kidney damage, urinary tract stones, and the like. The occurrence of hyperuricemia and gout is related to genetic factors and environmental factors. Genetic factors mainly include genetic variations that affect uric acid production and excretion, such as xanthine oxidase genes, renal uric acid transporter genes, and the like. Environmental factors mainly include high purine diet, alcoholism, obesity, hypertension, kidney disease, drugs, etc. The mechanisms of hyperuricemia and gout involve the formation and deposition of urate crystals, activation of inflammatory reactions, increased oxidative stress, impairment of endothelial function, and the like. In recent years, with economic development and lifestyle changes, the prevalence trend of hyperuricemia and gout is rising and younger. The global hyperuricemia and gout patients were statistically about 9.3 hundred million, and it is expected that 2025 would reach 11.8 hundred million people. The total prevalence of hyperuricemia in China is 13.3 percent, about 1.86 hundred million people, and the total prevalence of gout is 1.1 percent, about 0.15 hundred million people. Hyperuricemia and gout not only affect the quality of life of patients, but also are closely related to the onset of various chronic non-infectious diseases, such as cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Therefore, the method has important clinical significance and public health value in timely diagnosing and treating hyperuricemia and gout. Current methods of treatment mainly include drug therapy and non-drug therapy. The medicine is mainly divided into two stages, namely an acute stage and a remission stage, wherein the acute stage is mainly used for diminishing inflammation and relieving pain, and the remission stage is mainly used for reducing uric acid level. Non-drug therapies mainly include improving lifestyle, controlling diet, reducing weight, increasing exercise, etc. The combination of the drug therapy and the non-drug therapy can effectively control the development of hyperuricemia and gout and prevent the occurrence of complications. The main medicines for clinically treating hyperuricemia and gout at present are as follows: The main medicines for clinically treating hyperuricemia and gout at present comprise xanthine oxidase (XDH) inhibitors, which can reduce uric acid generation and blood uric acid level by inhibiting xanthine oxidase, and are suitable for patients with increased uric acid generation. Commonly used drugs are allopurinol and febuxostat. Allopurinol is a first-line uric acid reducing drug, the initial dose is 50-100 mg/d, the maximum dose is 800 mg/d, and the dosage is required to be adjusted according to renal function. Although the Chinese medicine has obvious curative effect and low price, the Chinese medicine should be especially concerned about the hypersensitivity (the incidence rate of the hypersensitivity in Taiwan province is 2.7%) in Chinese people, and once the mortality rate is up to 30%. It has been confirmed that allopurinol hypersensitivity occurs together with HLA-B 5801 Has obvious correlation, and the frequency of carrying the genotype by Han people is 10% -20%. Febuxostat is a specific xanthine oxidase inhibitor with an initial dose of 20 mg/d and a maximum dose of 80 mg/d, suitable for renal insufficiency patients, but should still be concerned about its potential cardiovascular risk. Disclosure of Invention The invention designs corresponding siRNA aiming at XDH, and effectively transmits the siRNA to the liver by coupling GalNAc to interfere with XDH mRNA at the liver part, thereby effectively reducing the expression of XDH protein, reducing the synthesis of uric acid and further playing a role in treating hyperuricemia. The XDH gene of the present invention is a gene shown in Genbank accession number NM-000379.4. The first aspect of the invention discloses an siRNA for inhibiting xanthine oxidase gene expression, which comprises a sense strand and an antisense strand,