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NOVEL AMYLOID FIBRIL FORMATION INHIBITOR

Foreign code F170008947
File No. (S2015-1616-N0)
Posted date Feb 2, 2017
Country WIPO
International application number 2016JP067373
International publication number WO 2016199892
Date of international filing Jun 10, 2016
Date of international publication Dec 15, 2016
Priority data
  • P2015-117150 (Jun 10, 2015) JP
Title NOVEL AMYLOID FIBRIL FORMATION INHIBITOR
Abstract The purpose of the present invention is to provide a therapeutic agent that is more effective in refractory amyloidosis. More specifically, it is to provide a novel substance that is highly safe and has a TTR protein amyloid fibril formation-inhibiting effect with which it is possible to inhibit the formation of amyloid fibrils better than conventional therapeutic agents. Provided by the invention is an amyloid fibril formation inhibitor containing as an active ingredient a complex comprsing a conjugate (GUG-β-CDE) of glucuronylglucosyl-β-cyclodextrin (GUG-β-CyD) and polyamide amine dendrimer having an alkylene diamine as the core and RNA that causes RNA interference in the mRNA of transthyretin (TTR). Also provided by the present invention is a pharmaceutical composition for the prevention and/or treatment of amyloidosis including the amyloid fibril formation inhibitor.
Outline of related art and contending technology BACKGROUND ART
Amyloidosis is, the polymerization of a protein having β - sheet structure (amyloid) or insoluble amyloid fibrillar form referred to as amyloid fibrils, deposited in a living body refers to a group of diseases that lead to tissue injury. Is in the pathologist Virchow Germany, iodo-violet staining tissue specimens of amyloidosis found. From this result, Virchow deposited materials include polysaccharides as the tissue is being coupled, this' starch-like material 'that is' amyloid' designated, amyloidosis caused by amyloid deposition conditions may be referred to as proposed. Subsequent studies, the main component of the amyloid to form fibrils polymerized nylon-like protein, such as serum amyloid P amyloid is included in the glycosaminoglycan component is known. At present, amyloid is' Congo red staining to orange-red staining, observed under a polarizing microscope strongly shiny green birefringence does not cause tangles 8-15 nm width integrated from branch ' and defined.
The deposition of amyloid fibrils and cause organ failure is amyloidosis, familial amyloid polyneuropathy (familial amyloid polyneuropathy; FAP), Alzheimer's disease, Creutzfeld, Jakob disease (mad cow disease), amyloid-like material may accumulate within the cell including Huntington's disease such as hereditary neurodegenerative disease and a variety of diseases. Among them FAP is, peripheral nerve, autonomic nerve, kidney, various organs such as the skin systemic amyloid deposits in the papermaking machine, in the form of autosomal dominant hereditary systemic amyloidosis and genetic penetrate, Japan, particularly Kyushu and in the middle portion in a region where a number of cases that have been identified. 1952 Human FAP Portuguese year since the first reported cases, various countries in the world from case report has been made in the same manner. Amyloid fibrils cause FAP is, mainly, transthyretin (TTR) serum proteins with mutations in the configured.
Is normal TTR, β - sheet structure and three-dimensional structure containing a large amount, liver, brain choroid plexus, retina, pancreatic α cells and the like is produced, in particular 90% or more is said to be produced in the liver. Is normal TTR, tetramer (T4) to form a thyroxine and retinol-binding protein (RBP) via a vitamin A as a transporter of the role of. Variants of the normal TTR, so far have been reported and include one or more 100, structural stability is low, from a tetramer to monomer susceptible to structural changes has been elucidated.
Than at Climate FAP is, due to the Val30Met types of mutations in a protein TTR FAP. And the properties of the main FAP, bilateral symmetry from the end of the ascending limb sensory disorders multiple sclerosis and neuritis autonomic neuropathy (alternating diarrhea and constipation, orthostatic hypotension, dysuria and the like) and, each of these is due to nerve damages caused by amyloid. Then, heart, kidney, become significant amyloid deposition to the alimentary canal, dysfunction of these organs. In general, from the latter half 30 20 margin 10 years develop in margin becomes unable to walk, 10 in the course of a year the number of heart failure, renal failure is a disease of poor prognosis such as die, also designated by the ministry of health and welfare of the particular disease which is one of the intractable.
Mutant TTR FAP protein can result in, low normal TTR structural stability compared to proteins, β - sheet structure in the molecule of insoluble amyloid fibrils associated with each other to form said to be the deposit of tissue. For treatment of FAP, about 90% or more TTR mutations produced in the liver from liver transplantation treatment is being performed. On the other hand, FAP that amyloid fibril formation mechanism based on a method for the treatment, the deviation of the tetramer (dissociation) molecule such as inhibition of TTR has been attempted (non-patent document 1 and 2).
In addition, by the present inventors, sugar, peptide or polyethylene glycol-modified cyclodextrin derivatives as an active ingredient that amyloid fibril formation inhibitor has been proposed (patent document 1). Wherein, the modified cyclodextrins derivatives as an example, 6-O-α - (4-O-α-D - glucuronyl) - β - cyclodextrin and 6-O-α - glycosylation -D- maltosyl - β - cyclodextrin is disclosed. In addition, by the present inventors, poly (amidoamine) dendrimer core alkylenediamines as an active ingredient that amyloid fibril formation inhibitor has been proposed (patent document 2). Further, by the present inventors, (G2) and polyamide amine dendrimers 6-O-α - (4-O-α-D - glucuronyl) - β - cyclodextrin -D- conjugate of glycosylation (GUG-β-CDE) and, with respect to TTR siRNA and complexes (siTTR), suppression of expression of the TTR and reported, in which, as a carrier for siRNA GUG-β-CDE of which has been proposed for use (non-patent document 3).
However, therapeutic agents for refractory amyloidosis alone is sufficient to effect a clinically effective treatment for development of therapeutics is still have not been successful. Therefore, using both the advantages of the present invention is believed to be a combination therapy with the drug, in this case drug interaction by various problems such as occurrence of the adverse effect is a possibility that the point is produced. Therefore, the agent is a more effective treatment effect has been demanded.
Scope of claims (In Japanese)[請求項1]
シクロデキストリンとポリアミドアミンデンドリマーとの結合体と、トランスサイレチンのmRNAに対してRNA干渉を起こすRNAとからなる複合体を有効成分として含むアミロイド線維生成抑制剤。
[請求項2]
前記シクロデキストリンが、グルクロニルグルコシル-β-シクロデキストリン(GUG-β-CyD)である請求項1に記載のアミロイド線維生成抑制剤。
[請求項3]
前記RNAが、shRNAまたはsiRNAである、請求項1又は2に記載のアミロイド線維生成抑制剤。
[請求項4]
前記RNAが、shRNAである請求項3に記載のアミロイド線維生成抑制剤。
[請求項5]
前記結合体が、グルクロニルグリコシル-β-シクロデキストリンとポリアミドアミンデンドリマーとの結合体(GUG-β-CDE)である、GUG-β-CDE(G2, DS 1.2)、GUG-β-CDE(G2, DS 1.8)、GUG-β-CDE(G2, DS 2.5)、又はGUG-β-CDE(G2, DS 4.5)である請求項2~4のいずれか一つに記載のアミロイド線維生成抑制剤。
[請求項6]
前記複合体における、GUG-β-CDE/RNAのチャージ比が、20~100である請求項2~5のいずれか一つに記載のアミロイド線維生成抑制剤。
[請求項7]
請求項1~6のいずれか一つに記載のアミロイド線維生成抑制剤を含むアミロイドーシスの予防及び/又は治療のための医薬組成物。
[請求項8]
前記アミロイドーシスが、家族性アミロイドーシスポリニューロパチー(FAP)、アルツハイマー病、老人性全身性アミロイドーシス(SSA)、又はAAアミロイドーシスである請求項7に記載の医薬組成物。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION KUMAMOTO UNIVERSITY
  • Inventor
  • JONO, Hirofumi
  • ARIMA, Hidetoshi
  • ANDO, Yukio
  • MOTOYAMA, Keiichi
  • HIGASHI, Taishi
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN 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 IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA 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 RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ 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 KM ML MR NE SN ST TD TG
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