Top > Search of International Patents > METHOD FOR SCREENING OF THERAPEUTIC AGENT FOR HYPERLIPEMIA

METHOD FOR SCREENING OF THERAPEUTIC AGENT FOR HYPERLIPEMIA

Foreign code F110003178
File No. A261-11WO
Posted date Jun 22, 2011
Country WIPO
International application number 2010JP070959
International publication number WO 2011065389
Date of international filing Nov 25, 2010
Date of international publication Jun 3, 2011
Priority data
  • P2009-269593 (Nov 27, 2009) JP
Title METHOD FOR SCREENING OF THERAPEUTIC AGENT FOR HYPERLIPEMIA
Abstract Disclosed are: a more highly safe treatment method for hyperlipemia; and a therapeutic agent for hyperlipemia. Specifically disclosed are: a novel method for screening for a therapeutic agent for hyperlipemia, more specifically a method for screening for a substance that can inhibit the production or function of ganglioside, particularly GM3, or inhibit the activity or expression of a GM3 synthase to decrease a blood lipid level; a pharmaceutical composition which can inhibit the production of ganglioside, particularly GM3, or the like specifically and is therefore effective for the treatment of hyperlipemia; and others.
Outline of related art and contending technology BACKGROUND ART
Myocardial infarction, cerebral infarction related cardiovascular disease such as arteriosclerosis has been increasing every year, one of the main causes of death in adults is 1. Although a variety of causes of arteriosclerosis but, hyperlipidemia (hypercholesterolemia, hypertriglyceridemia and the like) is one of the most important causes being 1. The treatment of hypercholesterolemia, HMG-CoA reductase inhibitor (in particular the statin drug), agent such as anion exchange resin is used in the formulation. However, these agents are in addition to the biosynthesis of cholesterol ubiquinone Dolby recall, biomolecules such as heme A maintenance of functions of the components needed for also inhibit biosynthesis, due to this concern about side effects.
In recent years, a variety of metabolic diseases induced by obesity (insulin resistance, 2 diabetes mellitus, hyperlipidemia, arteriosclerosis, fatty liver and the like) sphingolipids in the importance of glycolipids (glycosphingolipid: GSL) has been revealed. As a basic skeleton of the ceramide GSL various sugar chain is added in the group of molecules, or of all the cells in the blood are present in the cell membrane. As the starting point is the body GSL biosynthesis by an enzymatic reaction series (Fig. 1) is. Is referred to as sialic acid GSL , GM3 synthase (sialic acid transferase I: SAT-I) synthesized from lactosylceramide (LacCer) by GM3 (Fig. 1) and the starting point. Which is an initial stage of the biosynthetic pathway GSL glucosylceramide (GlcCer) biosynthesis enzyme inhibitors include, non-patent document 1 D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) (), (1R,2R) -nonanoic acid[ 2-(2,3-dihydro-benzo [1,4] dioxin-6-yl) -2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-l-tartaric acid salt (Genz-123346) D-threo-PDMP of the analog, and the like N-(5-adamantane-1-yl-methoxy) -pentyl-1-deoxynojirimycin (AMP-DNM). These inhibitors is, obese model animal and in vitro to improve insulin resistance, can have an effect of improving fatty liver, further serum triglyceride, free fatty acids (and cholesterol in bile from the liver is reduced such as to promote excretion of cholesterol into (i.e. activation of the reverse cholesterol transfer system) or the like has been reported (non-patent document 2-7), the clinical application aiming at the development is in progress.
However, in the knockout mouse of the glucosylceramide synthase is embryonic lethal since were reported to be (non-patent document 8), inhibitor of this enzyme is a fear that it could potential side effects. On the other hand, the lifetime of the knockout mouse of the GM3 synthase to be comparable to the wild-type (non-patent document 9) from the, adverse effects caused by inhibition of GM3 synthase is of little expected.
Organ responsible for insulin (muscle, liver and adipose tissue) is expressed GSL, glucosylceramide (GlcCer), lactosylceramide (LacCer), ganglioside GM3 and GM2 as in a wide variety. Yamashita et al. GM3 synthase (SAT-I) gene defect in the mice and, in these mice, shown in Fig. 1 a- and b- series ordinarily not express gangliosides, as well as a high-fat diet load at the onset of insulin resistance as compared to wild-type mice, SAT-I deficient mice in alleviating insulin resistance are reported (non-patent document 9).
Inokuchi J & Radin N (1987) J. Lipid Res. 28, 565-571
Tagami S, Inokuchi Ji J, Kabayama K, Yoshimura H, Kitamura F, Uemura S, Ogawa C, Ishii A, Saito M, Ohtsuka Y, et al. (2002) J Biol Chem 277, 3085-3092
Zhao H, Przybylska M, Wu IH, Zhang J, Siegel C, Komarnitsky S, Yew NS, & Cheng SH (2007) Diabetes 56, 1210-1218
Zhao H, Przybylska M, Wu IH, Zhang J, Maniatis P, Pacheco J, Piepenhagen P, Copeland D, Arbeeny C, Shayman JA, et al. (2009) Hepatology 50, 85-93
Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van Eijk M, Dubbelhuis PF, Aten J, Kuipers F, Serlie MJ, Wennekes T, et al. (2007) Diabetes 56, 1341-1349
van Eijk M, Aten J, Bijl N, Ottenhoff R, van Roomen CP, Dubbelhuis PF, Seeman I, Ghauharali-van der Vlugt K, Overkleeft HS, Arbeeny C, et al. (2009) PLoS One 4, e4723. Epub 2009 Mar 4723
Bijl N, van Roomen CP, Triantis V, Sokolovic M, Ottenhoff R, Scheij S, van Eijk M, Boot RG, Aerts JM, & Groen AK (2009) Hepatology 49, 637-645
YAMASHITA, T., et al, Proc. Natl. Acad. Sci. USA, Vol. 96, pp. 9142-9147, 1999
Yamashita T, Hashiramoto A, Haluzik M, Mizukami H, Beck S, Norton A, Kono M, Tsuji S, Daniotti JL, Werth N, et al. (2003) Proc Natl Acad Sci U S A 100, 3445-3449
Scope of claims (In Japanese)請求の範囲 [請求項1]
 血中脂質レベル低下作用を示す物質のスクリーニング方法であって、以下:
 (i) 被験物質の存在下または非存在下で、GM3合成酵素とその基質とを接触させる工程、
 (ii) GM3合成量を低下させる被験物質を選択する工程、
 (iii)選択された被験物質を非ヒト動物に投与する工程、および
 (iv) 非ヒト動物の血中脂質レベルを測定する工程
を含む、スクリーニング方法。

[請求項2]
 血中脂質レベル低下作用を示す物質のスクリーニング方法であって、以下:
 (i) 被験物質とGM3合成酵素を発現する細胞とを接触させる工程、
 (ii) GM3合成酵素の発現量を低下させる被験物質を選択する工程、
 (iii)選択された被験物質を非ヒト動物に投与する工程、および
 (iv) 非ヒト動物の血中脂質レベルを測定する工程
を含む、スクリーニング方法。

[請求項3]
 前記GM3合成酵素を発現する細胞が、脂肪細胞、肝細胞、血管内皮細胞、血管平滑筋細胞、骨格筋細胞、上皮細胞、神経細胞、繊維芽細胞、単球細胞、マクロファージからなる群より選択される、請求項2に記載の方法。

[請求項4]
 前記GM3合成酵素を発現する細胞が、遺伝子組み換えにより作製された形質転換細胞である、請求項2に記載の方法。

[請求項5]
 さらに、血中コレステロールレベルおよび/またはトリグリセリドレベルを低下させる被験物質を選択する工程を含む、請求項1~4のいずれか1項に記載のスクリーニング方法。

[請求項6]
 前記非ヒト動物が通常よりも高い血中脂質レベルを有する、請求項1~5のいずれか1項に記載の方法。

[請求項7]
 前記非ヒト動物がマウスである、請求項1~6のいずれか1項に記載の方法。

[請求項8]
 ガングリオシドの産生を特異的に抑制する物質を含有する、高脂血症の治療に有効な医薬組成物。

[請求項9]
 前記ガングリオシドがGM3である、請求項8に記載の組成物。

[請求項10]
 GM3に対する抗体、GM3合成酵素阻害剤またはGM3合成酵素の発現を阻害する物質を含有する、高脂血症の治療に有効な医薬組成物。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • JAPAN SCIENCE AND TECHNOLOGY AGENCY
  • Inventor
  • INOKUCHI Jinichi
  • NAGAFUKU Masakazu
  • HAYAMIZU Hirotaka
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
Reference ( R and D project ) CREST Clarification of the Biological Functions of Sugar Chains and the Use of this Knowledge in Applied Technologies AREA
Please contact us by E-mail or facsimile if you have any interests on this patent.

PAGE TOP

close
close
close
close
close
close