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Oligomer nucleic acid for suppressing myd88 gene and its application

An oligomeric nucleic acid and gene technology, applied in the direction of recombinant DNA technology, microbial measurement/testing, DNA/RNA fragments, etc., can solve the problems of differences in silencing effects, etc., and achieve the reduction of various inflammatory factors, high activity, and high specificity Effect

Active Publication Date: 2018-06-05
GUANGZHOU RIBOBIO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a variety of siRNAs can be designed for different fragment positions of the same gene, and the silencing effects are significantly different

Method used

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  • Oligomer nucleic acid for suppressing myd88 gene and its application
  • Oligomer nucleic acid for suppressing myd88 gene and its application
  • Oligomer nucleic acid for suppressing myd88 gene and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 6

[0038] The present invention optimizes the design for different positions in the CDs region of the MYD88 gene, and after preliminary experiments, selects 9 pairs of siRNAs for human and mouse homologous genes for screening tests. Finally, it was found that siRNA-M8-04 containing the nucleotide sequence of "3'GCCUCCUCUACCUGAAACU 5'" in the antisense strand had the strongest inhibitory effect on MYD88 gene mRNA expression, and the mRNA silencing efficiency of MYD88 gene reached 84% (Example 2). In western blotting experiments, the expression level of MYD88 protein was significantly decreased after adding siRNA-M8-04 compared with blank and negative control groups, and the difference was significant (P<0.05) (Example 3). After adding siRNA-M8-04 to cells stimulated by IL 1-α, compared with adding negative control oligonucleotides, the contents of cellular inflammatory factors TNF, COX-2, and IL-1β were significantly decreased, indicating that siRNA-M8-04 has Eliminate inflammatio...

Embodiment 8

[0039]The study in Example 8 shows that after chemical modification, the stability of the siRNA of the present invention in serum is significantly improved. Example 9 is the test of siRNA in vivo in rats. The chemical modification containing the antisense strand "3'GCCUCCUCUACCUGAAACU 5'" or 5'-UCGAAACCCAUCUCCUCCG-3' was injected individually or mixed into the joint cavity of the arthritis model rats. The detection test of the content of inflammatory factors in the liquid showed that the oligonucleotide had obvious inhibitory effect on inflammation in rats.

[0040] The beneficial effects of the present invention are mainly reflected in: 1. The present invention uses gene silencing technology, and through a large amount of design, screening, analysis and verification, a class of oligonucleotides that have a significant inhibitory effect on MYD88 are found. In a class of hFLS cells, The inhibition efficiency reaches more than 84%, and the nucleic acid sequence having more than ...

Embodiment 1

[0050] The chemical synthesis of embodiment one oligomeric nucleic acid

[0051] (1) The RNA and modified oligonucleic acid monomers used in the examples are all obtained according to the following methods:

[0052] RNA nucleotides in oligonucleotides are prepared with 2’-O-TBDMS phosphoramidite monomers; DNA nucleotides are prepared with deoxynucleoside phosphoramidite monomers; nucleotide sugar modified nucleosides are prepared with 2’-OCH 3 , 2'-F, locked nucleic acid (LNA), open-loop nucleic acid (UNA), 5-methylcytosine, indole, 5-ethynyl uracil phosphoramidite monomer preparation; backbone phosphothionucleic acid with Beaucage reagent Or PADS reagent is prepared instead of iodine water; cholesterol, fluorescent labeling, sugar modification, and phosphorylated oligonucleotides are prepared from corresponding monomers; polypeptide-modified oligonucleotides are obtained by Michael addition reaction of sulfhydryl-modified oligonucleotides and polypeptides. Purchased from Sig...

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Abstract

The invention discloses oligomerization nucleic acid inhibiting an MYD88 gene. The oligomerization nucleic acid is double-strand RNA (ribonucleic acid), a basic group of the oligomerization nucleic acid comprises an antisense strand and a positive-sense strand, the antisense strand comprises SEQ. ID NO.12 components, more than 70% of the components are homologous, the positive-sense strand comprises oligomerization nucleic acid reversely and complementarily paired with the antisense strand, more than 50% of sequences are homologous, and the positive-sense strand and the antisense strand can form a double-strand structure after annealing. The invention further discloses DNA (deoxyribonucleic acid) containing the oligomerization nucleic acid, a carrier, a composition and an application of the oligomerization nucleic acid. The oligomerization nucleic acid has a remarkable inhibiting function for an MYD88, can achieve an inflammation inhibition function in an animal experiment, remarkably reduces various inflammatory factors and is a quite promising inflammation therapy medicine.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a kind of oligonucleotide for inhibiting MYD88 gene and its application. Background technique [0002] Osteoarthritis (OA) is one of the important causes of disability in the world, and approximately more than 10% of the elderly have symptoms of osteoarthritis. Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting approximately 0.5% to 1% of the world's adults, often causing joint damage and jeopardizing quality of life. A variety of inflammatory cytokines such as TNF-α, IL-1, IL-6, etc. are involved in the pathogenesis and progression of RA and OA, which promote joint destruction, synovitis, and angiogenesis by activating immune cells and inducing the production of metalloproteinases wait. [0003] MYD88 is a cytoplasmic soluble protein that is activated by TLRs (except TLR3) and is the main adapter protein in the TLRs signal transduction pathway. Exis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/113C12N15/11C12N15/63C12Q1/6883C12Q1/6886A61K31/7088A61P29/00A61P19/02A61P19/08A61P37/02A61P31/00A61P35/00A61P9/00A61P11/06A61P3/10
Inventor 张必良杨秀群王玮
Owner GUANGZHOU RIBOBIO
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