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A kind of small interfering nucleic acid and pharmaceutical composition and application thereof

A composition and drug technology, applied in the field of biomedicine, can solve the problems of poor stability of siRNA, easy to be degraded by nucleases, differences between target nucleic acid species, etc., and achieve inhibition of expression, prevention and/or treatment of dyslipidemia, total cholesterol, etc. and lower triglyceride levels

Active Publication Date: 2021-09-24
SUZHOU RIBO LIFE SCIENCE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are species differences in target nucleic acids, which increases the difficulty in the development of siRNA drugs targeting target nucleic acids. At the same time, the stability of siRNA is poor, and systemic drug delivery has the disadvantage of being easily degraded by nucleases.

Method used

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  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof
  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof
  • A kind of small interfering nucleic acid and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0086] The sequence of siRNA is as shown in Table 2, and the positive-sense strand nucleotide sequence numbered as siAN is as shown in SEQ ID NO.4, wherein the 1-19 nucleotide sequence is as shown in SEQ ID NO.4 in the human ANGPTL3 mRNA sequence (NM_014495.3) The target nucleic acid shown in ID NO.1 is identical; The antisense strand nucleotide sequence of this siRNA is shown in SEQ ID NO.5, and wherein 1-19 nucleotide sequence is as shown in SEQ ID NO.1 in table 1 The indicated target nucleic acids are complementary. The positive-sense strand nucleotide sequence numbered as siAN2 is shown in SEQ ID NO.7, wherein the 1-19 nucleotide sequence is identical to the target nucleic acid shown in SEQ ID NO.6 in the ANGPTL3 mRNA sequence; the reverse of the siRNA The nucleotide sequence of the sense strand is shown in SEQ ID NO.8, wherein the nucleotide sequence at positions 1-19 is complementary to the target nucleic acid shown in SEQ ID NO.6 in Table 1.

[0087] As shown in Table ...

Embodiment 1

[0095] This example is used to detect the inhibitory rate of siRNA obtained in Preparation Example 1 on the expression level of ANGPTL3 mRNA in vitro.

[0096] The human liver cancer cell line Huh7 was inoculated in 24-well plates with DMEM complete medium containing 10% fetal bovine serum at a seeding density of 4×10 5 Cells / well, 0.5mL culture medium per well, culture overnight at 37°C.

[0097] Aspirate the cell culture medium in the 24-well plate, and add 0.5 mL Opti-MEM serum-free medium to each well. Dilute 1.5 μL of the siRNA in Preparation Example 1 and Preparation Example 2 at a concentration of 20 μM with 50 μL Opti-MEM serum-free medium; add 1 μL Lipofectamine TM 2000 (Invitrogen Company) was diluted in 50 μL Opti-MEM serum-free medium, incubated at room temperature for 5 minutes after mixing; mixed diluted siRNA and diluted Lipofectamine TM 2000, mix gently, and let stand at room temperature for 20 minutes to allow complex formation. Add the above final mixed solu...

preparation example 2

[0106] The siRNA obtained after chemical modification of the siRNA sense strand and antisense strand numbered siNC is shown in Table 5, and the number is siNC-M; the four groups of siRNA obtained after chemical modification of the siRNA sense strand and antisense strand numbered siAN are shown in Table 5. 5, respectively numbered siAN-M1, siAN-M2, siAN-M3, siAN-M4. Wherein (M) represents that the pentose group in the nucleotide residue on its left side is 2'-methoxyribose group, (F) represents that the pentose group in the nucleotide residue on its left side is 2' - Fluorinated ribose; S represents that the phosphate group between the deoxyribonucleotide residues dTdT on the left and right sides is a phosphorothioate group.

[0107] table 5

[0108]

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Abstract

The present disclosure relates to a small interfering nucleic acid and a pharmaceutical composition and uses thereof. The siRNA contains a sense strand and an antisense strand, the sense strand contains a nucleotide sequence as shown in SEQ ID NO.2, and the antisense strand contains a sequence such as The nucleotide sequence shown in SEQ ID NO.3; and the phosphate group and / or ribose group in the phosphate-sugar skeleton of the siRNA is a phosphate group and a ribose group with or without a modification group. The present disclosure provides a brand-new high-efficiency siRNA and a pharmaceutical composition thereof, which can effectively prevent and / or treat dyslipidemia.

Description

technical field [0001] The present disclosure relates to the technical field of biomedicine, in particular to a small interfering nucleic acid (siRNA), a pharmaceutical composition and uses thereof. Background technique [0002] Dyslipidemia, also known as hyperlipidemia, is a systemic disease in which fat metabolism or operation is abnormal, making plasma lipids higher than normal. The clinical manifestations of hyperlipidemia mainly include two aspects: (1) xanthoma caused by lipid deposition in the dermis; (2) atherosclerosis caused by lipid deposition in the vascular endothelium, resulting in coronary heart disease and peripheral Vascular disease, etc. According to reports, approximately 35% of type 2 diabetes patients worldwide also suffer from dyslipidemia; in addition, 18 million people suffer from hypertriglyceridemia in hyperlipidemia. The prevalence of dyslipidemia among people aged 18 and over in my country is about 18.6%, and even nearly 10% of children have el...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/113A61K31/713A61K47/18A61K47/10A61K47/28A61P3/06A61P9/10
CPCA61K47/10A61K47/18A61K47/28C12N15/1136C12N2310/321C12N2310/322C12N2310/315C12N2310/14A61K31/713A61P3/06A61P9/10
Inventor 张鸿雁高山
Owner SUZHOU RIBO LIFE SCIENCE CO LTD
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