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Small interfering nucleic acid and pharmaceutical composition and application thereof

A nucleotide and nucleotide sequence 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., to achieve inhibitory content, prevention and/or treatment of blood lipids abnormal effect

Active Publication Date: 2018-07-03
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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  • Small interfering nucleic acid and pharmaceutical composition and application thereof
  • Small interfering nucleic acid and pharmaceutical composition and application thereof
  • Small interfering nucleic acid and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0106] The sequence of siRNA is shown in Table 2, and the nucleotide sequence of the sense strand numbered siAP-1 is shown in SEQ ID NO.6, where the nucleotide sequence of positions 1-19 is similar to the human APOC3 mRNA sequence (NM_000040.1). The target nucleic acid shown in SEQ ID NO.1 is the same; the nucleotide sequence of the antisense strand of the siRNA is shown in SEQ ID NO.7, and the nucleotide sequence of positions 1-19 is the same as that shown in SEQ ID NO.1 in Table 1. The indicated target nucleic acids are complementary. The nucleotide sequence of the sense strand numbered siAP-2 is shown in SEQ ID NO. 8, wherein the nucleotide sequence of positions 1-19 is the same as the target nucleic acid shown in SEQ ID NO. 2 in the APOC3 mRNA sequence; The nucleotide sequence of the antisense strand is shown in SEQ ID NO. 9, wherein the nucleotide sequence at positions 1-19 is complementary to the target nucleic acid shown in SEQ ID NO. 2 in Table 1. The nucleotide sequen...

Embodiment 1

[0114] This example is used to detect the inhibition rate of the siRNA obtained in Preparation Example 1 on the expression level of APOC3 mRNA in vitro.

[0115] The human hepatoma cell line Huh7 was inoculated into a 24-well plate with DMEM complete medium containing 10% fetal bovine serum at a density of 4×10 5 Cells / well, 0.5mL medium per well, cultured overnight at 37°C.

[0116] Aspirate the cell culture solution in the 24-well plate, and add 0.5 mL of Opti-MEM serum-free medium to each well. Dilute 1.5 μL of the siRNA in preparation example 1 at a concentration of 20 μM with 50 μL of Opti-MEM serum-free medium; add 1 μL of Lipofectamine TM 2000 (Invitrogen) diluted in 50μL Opti-MEM serum-free medium, mixed and incubated at room temperature for 5 minutes; mixed diluted siRNA and diluted Lipofectamine TM 2000, mix gently and let stand at room temperature for 20 minutes to allow complex formation. The final mixed solution was added to a 24-well plate seeded with Huh7 cells ...

preparation example 2

[0125] The siRNAs obtained after chemical modification of the siRNA sense strand and antisense strand numbered siNC are shown in Table 5, numbered as siNC-M; 3 groups of siRNAs obtained after chemical modification of the siRNA sense strand and antisense strand numbered siAP-1 As shown in Table 5, they are numbered siAP-1-M1, siAP-1-M2, and siAP-1-M3. The three groups of siRNAs obtained after chemical modification of the siAP-2 siRNA sense strand and antisense strand are shown in Table 5, respectively numbered siAP-2-M1, siAP-2-M2, and siAP-2-M3. The three groups of siRNAs obtained after chemical modification of the siAP-3 siRNA sense strand and antisense strand are shown in Table 5, respectively numbered siAP-3-M1, siAP-3-M2, and siAP-3-M3. The three groups of siRNAs obtained after chemical modification of the siAP-4 siRNA sense strand and antisense strand are shown in Table 5, respectively numbered siAP-4-M1, siAP-4-M2, siAP-4-M3.

[0126] Where m represents the pentose group o...

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Abstract

The invention relates to a small interfering nucleic acid and a pharmaceutical composition and an application thereof. The siRNA contains complementary positive-sense strand and antisense strand, wherein the positive-sense strand contains nucleotide sequences as shown in SEQ ID NO.24, SEQ ID NO.26, SEQ ID NO.28 or SEQ ID NO.30, and the antisense strand contains nucleotide sequences as shown in SEQID NO.25, SEQ ID NO.27, SEQ ID NO.29 or SEQ ID NO.31. A phosphoric acid framework and / or nucleotide pentose in a phosphoric acid-sugar framework of the siRNA has or does not have modifying groups. The invention provides a brand new efficient siRNA and a pharmaceutical composition thereof, and the siRNA can prevent and / or treat dyslipidemia effectively.

Description

Technical field [0001] The present disclosure relates to the field of biomedicine technology, in particular, to a small interfering nucleic acid (siRNA), a pharmaceutical composition and their uses. Background technique [0002] Dyslipidemia, also known as hyperlipidemia, is a systemic disease in which fat metabolism or function is abnormal, which makes 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 and so on. 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 in people aged 18 and over in my country is about 18.6%, and even nearly 10% of children have e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61K48/00A61K31/713A61P3/06A61P9/10
CPCA61K31/713C12N15/113C12N2310/14C12N2310/315C12N2310/32C12N2320/30
Inventor 张鸿雁高山
Owner SUZHOU RIBO LIFE SCIENCE CO LTD
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