Composition for treating eye diseases by double-target/multi-target small nucleic acid and applications of composition

A technology of small nucleic acid and composition, applied in metabolic diseases, gene therapy, sensory diseases, etc., can solve the problems of limited therapeutic effect of VEGF antagonists

Active Publication Date: 2013-04-03
SUZHOU SIRNAOMICS BIOPHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Numerous studies confirm that VEGF plays a central role in neovascularization, but puzzlingly, the therapeutic effect of VEGF antagonists is limited

Method used

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  • Composition for treating eye diseases by double-target/multi-target small nucleic acid and applications of composition
  • Composition for treating eye diseases by double-target/multi-target small nucleic acid and applications of composition
  • Composition for treating eye diseases by double-target/multi-target small nucleic acid and applications of composition

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment 1

[0057] Specific Example 1: Small nucleic acids with a length of 25 base pairs are better than small nucleic acids with a length of 21 base pairs

[0058] Although the initial studies were mainly using chemically synthesized 19 and 21 base pair snucleic acid duplexes, there is evidence that 23, 25, and 27 base pair snucleic acid duplexes are more The oligonucleotide duplex showed better inhibitory activity. The potential for interferon-activating effects of longer small nucleic acids (23 base pairs or longer) is a cell-type-dependent phenomenon. We found that 25 bp duplexes with blunt ends had the best inhibitory effect in MBA-MD-435 or DLD-1 cell lines and tumor-bearing animal models. We detected the 25 base pair small nucleic acid hVEGF-25c (sense strand: 5'-CACAACAAAUGUGAAUGCAGACCAA-3'; antisense strand: 5'-UUGGUCUGCAUUCACAUUUGUUGUG-3') targeting the human VEGF gene, and compared with the The 21 base pair VEGF sequence hVEGF-21a (sense strand: 5'-UCGAGACCCUGGUGGACAU...

specific Embodiment 2

[0059] Specific Example 2: Selection of Small Nucleic Acids Specific to Human and Mouse VEGF mRNA

[0060] Based on a proprietary computer-based algorithm, we designed small nucleic acids (Table 1) targeting VEGF with the following characteristics: a. Optimal thermodynamic characteristics; b. Enhanced binding ability to RISC; c. Elimination of immune activation structures d. has human-mouse homology; e. searches for sequences through existing intellectual property rights; f. uses blast to avoid "off-target effects"; g. can be used as a small nucleic acid cocktail drug. The most effective small nucleic acids against each gene were selected by Q-RT-PCR (MyiQ, Bio-Rad) detection. The 25 base pair siRNAs used for in vitro cell culture studies were synthesized by Qiagen (Germantown, MD) and larger quantities were synthesized by Dharmacon (Bolder, CO) for in vivo studies in animal disease models. The cell line used to screen the most effective siRNA should be one that expres...

specific Embodiment 3

[0061] Specific Example 3: Selection of Small Nucleic Acids Specific for Human and Mouse VEGFR-2 mRNA

[0062] According to a proprietary computer-based algorithm, we designed small nucleic acids for VEGFR-2 (Table 2), which have the following characteristics: a. Optimum thermodynamic characteristics; b. Enhanced binding ability to RISC; c. Activation domain; d. Human-mouse homology; e. Search sequence through existing intellectual property rights; f. Use blast to avoid "off-target effect"; g. Can be used as a small nucleic acid cocktail drug. The most effective small nucleic acids against each gene were selected by Q-RT-PCR (MyiQ, Bio-Rad) detection. The 25 base pair siRNAs used for in vitro cell culture studies were synthesized by Qiagen (Germantown, MD) and larger quantities were synthesized by Dharmacon (Bolder, CO) for in vivo studies in animal disease models. The cell line used to screen the most effective small nucleic acid should be a cell line capable of expre...

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Abstract

The invention discloses a composition for treating eye diseases by double-target / multi-target small nucleic acid and applications of the composition. The composition comprises two small nucleic acid molecules and a medicinal carrier, target genes of the two small nucleic acid molecules are selected from two of VEGF (vascular endothelial growth factor) gene, VEGFR2 (vascular endothelial growth factor receptor2) gene and TGF-b1 (transforming growth factor-beta1) gene; or the composition comprises three small nucleic acid molecules and a medicinal carrier, and target genes of the three small nucleic acid molecules are respectively VEGF gene, VEGFR2 gene and TGF-b1 gene. The composition can be used for effectively treating eye diseases by virtue of ribonucleic acid interference (RNAi) mediated inhibitor gene expression and biochemical pathway, and can be prepared to form a medicament for treating eye diseases, including proliferatived diabetic retinophathy, diabetic macular edema, herpes simplex interstitial keratitis, age-related macular degeneration, uveitis and the like.

Description

[0001] technical field [0002] The present invention mainly relates to a nucleotide drug, in particular to a dual-target / multi-target small nucleic acid cocktail drug, which uses RNA interference (RNAi) technology to treat eye diseases such as diabetic retinopathy. Background technique [0003] Diabetic retinopathy is the most common cause of blindness in the working population worldwide. The disease primarily causes macular edema by damaging the small blood vessels in the light-sensitive retinal tissue of the eye, causing fluid to leak near the center of the retina, known as the spot. The spots provide central vision for activities such as reading, driving and recognizing faces, and in patients with macular edema, retinal tissue swells and can lead to blindness if left untreated. [0004] In addition to diabetic retinopathy, a number of other ocular diseases are also caused by excessive angiogenesis (NV), which is the abnormal proliferation and growth of blood vessels in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K31/7105A61K31/713A61K47/34A61P9/10A61P27/02A61P3/10A61P31/22
Inventor 陆阳徐军路阳唐盛高龙超峰陈小新谢称石
Owner SUZHOU SIRNAOMICS BIOPHARMACEUTICALS CO LTD
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