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Sugar chain-related gene and use thereof

a technology of sugar chain and related genes, applied in the direction of dna/rna fragmentation, peptide/protein ingredients, transferases, etc., can solve the problems of limited conventional study approaches and insufficient analysis of sugar chains, and achieve the effect of suppressing the fibrogenesis of physiological tissues

Inactive Publication Date: 2014-05-08
STELIC INST OF REGENERATIVE MEDICINE STELIC INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The agents effectively suppress fibrogenesis at the physiological tissue level, demonstrated through reduced expression of fibrogenesis markers and collagen deposition in animal models, showing therapeutic potential for various fibrotic diseases.

Problems solved by technology

They also suggested limitations of conventional study approaches.
Sugar chains have not been analyzed intensively because of the difficulty to perform structural analysis, etc.

Method used

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  • Sugar chain-related gene and use thereof
  • Sugar chain-related gene and use thereof
  • Sugar chain-related gene and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Assessment of the Target Sugar Chain-Related Gene Knockdown Effect of siRNAs and Anti-Fibrogenic Effect at the Gene Level in a Mouse Cardiomyopathy Model

[0322]A model prepared by intraperitoneal administration of Doxorubicin hydrochloride (DOX; Kyowa Hakko), as a standard mouse cardiomyopathy model, was used in this Example and those below. This mouse model is classical, but highly reproducible and simple. Thus, the model has been widely used as a cardiomyopathy model for elucidating pathological conditions, experimenting new therapeutics, or such (Longhu Li, Circulation (2006) 113: 535-543; Xiaoming Yi, Am J Physiol Heart Circ Physiol (2006) 290: H1098-H1102; Kang Y J, J Biol. Chem. 2000 May 5; 275(18): 13690-8; Nozaki N, Circulation (2004) 110: 2869-2874; Fisher P W, Circulation (2005) 111: 1601-1610).

[0323]The model mouse histologically develops fibrogenesis of the myocardial interstitium. This pathological findings is commonly observed in dilated cardiomyopathy, restrictive card...

example 2

Cardiac Hypertrophy-Suppressing Effect of GalNAc4S-6ST siRNA in a Mouse Cardiomyopathy Model

[0330]In this Example, the heart weights (mg) and body weights (g) of cardiomyopathy model mice were measured to calculate the heart / body weight ratio which is an indicator for cardiac hypertrophy. The cardiac hypertrophy-suppressing effect of the GalNAc4S-6ST (GalNac) siRNA was evaluated. Cardiac hypertrophy also serves as an indicator for tissue fibrotic change.

[0331]FIG. 1 shows the result of calculating the heart weight (mg) / body weight (g) ratios in the siRNA-treated group (n=4) and untreated group (n=4). The result showed that the ratio was 6.376±0.484 and 5.442±0.203 in the untreated and siRNA-treated groups, respectively. Thus, the significant reduction of the ratio was found in the siRNA-treated group as compared to the untreated group (p<0.05; t-test). This suggests that GalNac4S-6ST siRNA has the effect of suppressing pathological cardiac hypertrophy.

[0332]The agents of the present...

example 3

Assessment of Type I Collagen Deposition-Suppressing Effect of GalNAc4S-6ST siRNA in a Mouse Cardiomyopathy Model

[0333]In this Example, the type I collagen deposition (an indicator of fibrogenesis)-suppressing effect of GalNac4S-6ST siRNA was assessed using heart samples of cardiomyopathy model mice. Cardiac tissue samples were collected from the same mice as described in Example 1, and embedded in OCT compound (Miles), an embedding medium for cryosectioning. The samples were sliced into thin sections using Cryostat (Carl Zeiss). The resulting sections were fixed with acetone (Sigma Aldrich Japan) for ten minutes, and then washed with phosphate buffer. A rabbit antiserum anti-type I collagen (rabbit polyclonal antibody, 1:2,000 dilution; LSL) was added as the primary antibody, and the sections were incubated at room temperature for one hour. Then, a peroxidase-labeled goat anti-rabbit IgG antibody (1:200 dilution; Cappel) was added as the secondary antibody, and the sections were in...

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Abstract

As a result of dedicated studies, the present inventors succeeded in discovering, for the first time, that fibrogenesis could be suppressed at the physiological tissue level by inhibiting sulfation at position 4 or 6 of GalNAc, which is a sugar that constitutes sugar chains. Furthermore, the present inventors conducted studies using various disease model animals, and as a result, successfully demonstrated that inhibitors of sulfation at position 4 or 6 of GalNAc had therapeutic effects on diseases caused by tissue fibrogenesis (tissue fibrogenic disorders).

Description

TECHNICAL FIELD[0001]The present invention relates to inhibitors of fibrogenesis at the physiological tissue level by inhibiting sugar chain-related genes.BACKGROUND ART[0002]Intensive studies have been conducted on nucleic acids and proteins, revealing many findings. However, these studies also showed that there are only about 22,000 human genes and also that post-translational modification of proteins plays an important role in vivo. They also suggested limitations of conventional study approaches. In recent years, the importance of sugar chains has been rediscovered with the post-genome and post-proteomics trends (the journal “Nature” extensively featured sugar chains in Vol. 446 published in Apr. 26, 2007 (Non-patent Documents 1 to 7). Sugar chains have not been analyzed intensively because of the difficulty to perform structural analysis, etc. Although they are assumed to be involved in cancer, inflammation, immunity, viral infection, etc., at present, little is known about the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/113G01N33/50
CPCG01N33/5023C12N15/1137C12N9/13C12N2310/14C12Q1/48C12Q1/485G01N2333/91194A61K31/7105Y10T436/143333A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P13/08A61P13/10A61P13/12A61P15/10A61P17/00A61P19/02A61P19/04A61P21/00A61P21/04A61P25/00A61P25/02A61P25/16A61P25/18A61P25/28A61P27/02A61P29/00A61P3/00A61P31/14A61P31/20A61P37/02A61P37/08A61P43/00A61P7/00A61P7/02A61P9/00A61P9/04A61P9/06A61P9/10A61P3/10A61K38/43
Inventor YONEYAMA, HIROYUKIKOYAMA, JUNFUJII, MASATO
Owner STELIC INST OF REGENERATIVE MEDICINE STELIC INST