JP5485265B2 - Jnkシグナル伝達経路に対する、細胞透過性のペプチド性阻害剤の種々の、疾病を治療するための使用 - Google Patents
Jnkシグナル伝達経路に対する、細胞透過性のペプチド性阻害剤の種々の、疾病を治療するための使用 Download PDFInfo
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Description
(i)放射性ラベル、すなわち、放射性リン酸化、または硫黄、水素、炭素、窒素などによる放射性ラベル、
(ii)着色された色素(例えば、ジゴキシゲニン(digoxygenin)など)、
(iii)蛍光基(例えば、フルオレセインなど)、
(iv)化学発光基、
(v)固相における固定化のための基(例えば、Hisタグ、ビオチン、strepタグ、flagタグ、抗体、抗原など)、および、
(vi)上記(i)〜(v)に記載したラベルのうちの2つ以上のラベルの組み合わせ。
実施例1:JNK阻害剤配列の同定
JNKとの効果的な相互作用のために重要なアミノ酸配列を、公知のJNK結合ドメインJBD間の配列アラインメントによって同定した。IB1[配列番号13]、IB2[配列番号14]、c−Jun[配列番号15]、およびATF2[配列番号16]のJBD間の配列を比較することにより、低度に保存された8つのアミノ酸配列(図1A)を規定した。
配列番号1のC−末端を、2つのプロリン残基から成るリンカーを介して、HIV−TAT4g57に由来する配列番号5に記載の10個のアミノ酸の長さの担体ペプチドのN−末端(Vives et al., J Biol. Chem. 272: 16010 (1997))に共有結合させることによって、配列番号9に記載のJNK阻害剤融合蛋白質を合成した。このリンカーは、最大のたわみ性を可能にして、望ましくない2次的構造変化を回避するために用いたものである。この基本構造を調製して、L−IB1(s)(配列番号1)およびL−TAT[配列番号5]をそれぞれ指定した。
IB1(s)の19aaの長さのJBD配列が、JNK生物活性に与える影響を調査した。この19aa配列を、N−末端で、緑色蛍光蛋白質(GFP JBD19構成)に結合させ、この構成がIL1によって誘発された膵臓ベータ−細胞アポトーシスに与える効果を評価した。この形態のアポトーシスは、JBD1-280でトランスフェクションすることによって阻止されることが既に示されているが、当該技術分野において公知のERK1/2またはp38の特異的阻害剤は、これを、保護しなかった。
TATおよびTAT−IB1(s)ペプチド(「TAT−IBペプチド」)のL−およびD−鏡像異性体の、細胞の中に侵入する能力を評価した。フルオレセインに接合されたグリシン残基のN−末端を付加することによって、L−TAT、D−TAT、L−TAT−IB1(s)、およびD−TAT−IB1(s)ペプチド[それぞれ、配列番号5、6、9、および12]を標識化した。標識化されたペプチド(1μM)をTC−3細胞培養に添加し、これを、実施例3に記載したように維持した。所定の時間に何回か、細胞をPBSで洗浄し、冷却されたメタノール−アセトン(1:1)において、5分間固着させた後に、蛍光顕微鏡下で検査した。
ペプチドが、これらの標的転写因子のJNK−媒介性リン酸化に与える影響を、インビトロで調査した。活性化されていない、組み換えJNK1、JNK2、およびJNK3を、転写および翻訳ウサギ網赤血球溶解物キット(TRANSCRIPTION AND TRANSLATION rabbit reticulocyte lysate kit)(Promega)を用いて産生し、c−Jun、ATF2、およびElk1の固相キナーゼアッセイにおいて、単独、または、グルタチオン−S−転移酵素(GST)に融合させて、基質として用いた。
本明細書において規定されたL−TATまたはL−TAT−IB1(s)ペプチドが、ストレス刺激によって活性化されたJNKに与える影響を、UV−光が照射されたHeLa細胞またはIL−1処理されたPTC細胞からJNKをプルダウンするGST−Junを用いて、評価した。PTC細胞を上述のように培養した。10%のウシ胎仔血清、100μg/mLのストレプトマイシン、100単位/mlのペニシリン、および2mMのグルタミンが補充されたDMEM媒質中で、HeLa細胞を培養した。
本明細書において規定された細胞透過性のペプチドが、JNKシグナル伝達をインビボで阻止するかどうかを判定するために、我々は、異種のGAL4システムを用いた。上述の通りに培養されたHeLa細胞を、5xGAL−LUCレポーターベクターと、GAL−Jun発現構造(Stratagene)とで同時にトランスフェクトした。GAL−Jun発現構造は、GAL4DNA−結合ドメインに結合されたc−Jun(アミノ酸1〜89)の活性化ドメインを含む。
本発明のペプチドは、逆合成され、自然な蛋白質分解を妨げる全てのDアミノ酸ペプチド(すなわち全てのDレトロ−インベルソペプチド)であってよい。本発明の全てのDレトロ−インベルソペプチドは、ネイティブペプチドに似た機能的特性を有するペプチドを提供することになる。ここで、アミノ酸成分の側鎖は、ネイティブペプチドアラインメントに対応しているが、プロテアーゼ耐性の基幹を保持している。
ペプチドへテロ結合体(上述のキメラ配列を参照)を含むD−TAT−IB(s)レトロ−インベルソの、ネイティブL−アミノ酸類縁物質よりも長期の生物活性が示されている。これは、D−TAT−IB(s)ペプチドが、実施例5に示されるように、ネイティブプロテアーゼによる劣化から保護されているからである。
AP−1ダブル標識プローブ(5’−CGC TTG ATG AGT CAG CCG GAA−3’(配列番号101)を用いて、ゲルリターデイションアッセイを行った。5ng/mlのTNF−アルファで1時間処理された、または処理されていないHeLa細胞の核を抽出した。本発明に従って用いられるTATおよびL−TAT−IB1(s)ペプチドを、TNF−アルファの処理の30分前に添加した。特異的AP−1 DNA複合体を有するゲルの一部だけが示されている(標識化されていない特異的および非特異的競合物質との競合実験によって示されるように)。
実験の前日に、HepG2細胞を、3,000細胞/ウェルで播種した。その後、濃度が増大されたインターロイキン−1[IL−1ベータv)]または腫瘍壊死因子[TNFアルファ(●)](a)を添加して、JNKを30分間活性化させた。細胞を、20mMのヘペス(Hepes)、0.5%のトゥイーン(Tween)(pH7.4)において溶解させ、アルファスクリーン(AlphaScreen)JNKを処理した。(b)10ng/mlのIL−1によって誘発されたJNK活性のZ’が、384ウェル/プレート(n=96)において測定された。(c)化学的JNK阻害剤[staurosporin(○)およびSP600125(●)]による内因性IL−1ベータ−誘発性JNK活性の阻害。(d)配列番号9に記載のペプチド性阻害剤L−TAT−IB1(s)[ここでは、L−JNKi(v)と略記されている)および配列番号11に記載のD−TAT−IB1(s)(ここではD−JNKi(◆)と略記されている)およびJBD(●)(L−JNKIに対応しているが、TAT配列を有さない)]の、IL−1に依存する、JNK活性に与える影響。全てのパネルは、3つの独立した実験(n=3)を示すものである。
原理:アルファスクリーンとは、マイクロプレートフォーマットの生体分子相互作用を検査するために用いられる非放射性ビーズベースの技術である。頭文字ALPHAは、Amplified Luminescence Proximity Homogenous Assay(化学増幅型ルミネッセンスプロキシミティホモジニアスアッセイ)を表す。これは、「供与体」ビーズおよび「受容体」ビーズを近接させ、その後、化学的反応のカスケードが、増幅された信号を生成するように機能する生物学的相互作用を含む。
培養された宿主細胞(ヒト包皮繊維芽細胞(HFF))において、JNK阻害剤ペプチドXG−102(配列番号11)を試験化合物として用いて、本発明に従って使用されるIB(s)ペプチドおよび全てのDレトロ−インベルソIB(s)ペプチドの活性の判定を、試験した。ウイルスは、偏性細胞内寄生体であり、それらの生活サイクルを完結するためには機能している細胞環境を必要とする。すなわち、瀕死の細胞は、ウイルス複製を支援しない。
毒性の判定のために、培養細胞(ヒト包皮繊維芽細胞(HFF))を、96−ウェル組織培養プレート内に播種した。DMSO(5μMのXG−102(配列番号11)と同じレベル)、または、XG−102(配列番号11)を含有する培地を、幾つかの濃度(1、2、および5μM)で添加し、24時間保持した。
XG−102(配列番号11)が、投与量に依存した抗ウイルス作用を有していたかどうかを判定するために、標準的な1μMの投与量およびその大小近くの濃度範囲を試験した。
ヒト包皮繊維芽細胞(HFF)内の水痘帯状疱疹ウイルス(VZV)複製をXG−102(配列番号11)によって阻止する、XG−102の最小有効量を判定するために、HFFのコンフルエントな単分子層をVZV−BAC−Luc菌株で2時間培養し、その後、0.25μM、0.5μM、若しくは1.0μMの濃度のXG−102(配列番号11)、または陰性コントロール(XG−100,1.0μM)で、24時間処理した。ウイルス収量を、ルシフェラーゼアッセイによって測定した。試料を3部作成し、平均ルミネセンスを表示させた。エラーバーは、平均値からの標準偏差を示すものである。
慢性閉塞性肺疾患(COPD)の治療における、典型的な全てのDレトロ−インベルソIB(s)ペプチドXG−102(配列番号11)の活性を判定するために、XG−102(配列番号11)を、ブレオマイシン誘発性急性肺炎および腺維症の動物モデルにおいて用いる。ブレオマイシン誘発性炎症および腺維症の説明については、既に、文献に記載されている。本実験の目的は、皮下(s.c.)経路によるXG−102(配列番号11)が、気管支肺胞洗浄(BAL)、並びにブレオマイシン誘発性炎症および腺維症の肺における、好中球の動員(recruitment)に与える影響を、
−ブレオマイシンの単回投与(10mg/kg)の1日後、
−および、腺維症を発症した場合には、10日後に、調査することであった。
ブレオマイシンの鼻腔内単回投与によって、2つの投与量の試験化合物XG−102(配列番号11)、およびビヒクルコントロールを、s.c.で与え、マウスを、1日後および10日後に分析した。モデルに用いた動物は、グループ当たり10匹のC57BL/6マウス(8週齢)であった。
ケタミン−キシラジンの軽い麻酔の状態で、Bellon Laboratories社(Montrouge、フランス)からの生理食塩水中の硫酸ブレオマイシン(10mg/kg体重)、または生理食塩水を、容積40μLの鼻注入法によって、気道を介して与えた。ブレオマイシン誘発性炎症および腺維症のためにブレオマイシンを投与したグループには、ビヒクル、0.001mg/kgのXG−102(配列番号11)、および0.1mg/kgXG−102(配列番号11)が含まれる。ブレオマイシン誘発性炎症の経路は、皮下(s.c.)経路であり、投与は、単回投与として行った。ブレオマイシン誘発性腺維症のための経路は、皮下(s.c.)経路であり、投与は、10日間で3回行った。
気管を切開した後に、プラスチックのカニューレを挿入し、37°Cに加熱した0.3mlのPBS溶液を用いて、気腔を洗浄した。採取した試料を、直ちに2部に分けた。一方の第1の部分(上記2部の第1の洗浄に相当する1ml)は、媒介物質の測定のために用い、他方の第2の部分は、細胞判定に用いた(4ml)。最初の部分を、遠心分離させ(600gで10分間)、上清を分別し、媒介物質の判定まで、−80°Cで保存した。その後、細胞ペレットを、0.4mlの滅菌NaCl(0.9%)中に再懸濁させ、第2の部分と共にプールし、細胞計数に用いた。
BALの後、肺全体を取り出し、1mlのPBSを有するマイクロチューブ(Lysing matrix D, Q Bio Gene, Illkrich、フランス)の中に置いた。Fastprep(登録商標)システム(FP120, Q Bio Gene, Illkrich、フランス)を用いて、全ての肺組織抽出物を調製した。その後、この抽出物を遠心分離させ、上清を、媒介物質の測定、およびSircolコラーゲンアッセイ(France Biochem Division、フランス)を用いたコラーゲンアッセイを行うまで、−80°Cで保存した。
細胞の総数を、BAL液において、マラッセ(Malassez)血球計を用いて測定した。MGG Diff-quick(Dade Behring AG)で染色した後に、差別化した細胞の計数をサイトスピン調製(サイトスピン3、hermo Shandon)上で行った。標準的な形態基準を用いて、200の細胞について、差別化した細胞の計数を行った。
BALF中のTNFのレベルを、ELISAアッセイキット(Mouse DuoSet, R&D system、ミネアポリス、米国)を製造社の取扱説明に基づいて用いて、判定した。結果をpg/mlで報告する。
XG−102を投与した時のMPO−レベルを測定した。本実験において、ブレオマイシンの後には、MPOは、あまり誘発されなかった。さらに、XG−102は、肺のMPOレベルに影響しなかった。
BALおよび肺血流の後、標準的な顕微鏡分析のために、大きなローブ(葉)を、4%の緩衝ホルムアルデヒド中で固着させた。3−mの切片をヘマトキシリンおよびエオシン(H&E)で染色した。
A)第1の調査:ブレオマイシン(BLM)誘発性急性肺炎
グループ:ビヒクル、XG−102(配列番号11)0.001mg/kg、およびXG−102(配列番号11)0.1mg/kg
経路:s.c.経路、単回投与
a) 気管支肺胞洗浄空間における細胞動員
0.1mg/kgにおいて、XG−102(配列番号11)は、好中球動員、および炎症段階中に動員された細胞の総数を著しく低減させる。0.001mg/kgでは、XG−102(配列番号11)は、好中球の動員、または、他の種類の細胞が気管支肺胞腔の中に動員することに全く作用しなかった(代表的な一実験では、グループ当たりn=5匹のマウス;*,p<0.05;**,p<0.001)。
ミエロペルオキシダーゼ(MPO)は、宿主防御システムにおいて、重要な役割を果たしている。53kDaの2つの重鎖と15kDaの2つの軽鎖とから構成される、この140kDaの蛋白質は、1960年代に最初に発見された。MPOが、白血球の活性化に応答して、好中球および単球の顆粒から放出されることは、過酸化水素および塩化物イオンを、強力な酸化剤である次亜鉛素酸(HOCl)に変換させることを可能にする。MPOは、防御システムにおける重要な目的を果たすが、MPOは、また幾つかの炎症状態の原因にもなることを、様々な研究が示している。ここで、例えば、MPOレベルの増大は、冠動脈疾患に関連していることが示されている。さらに、組織MPOのレベルは、好中球の活性の状態を反映しており、好中球の組織への浸透の徴候を示す。
TNFのレベルを測定すると、XG−102(配列番号11)を投与した後は、BALF中のTNFのレベルは、減少する傾向が観察され、BLMの投与後は、TNFのレベルは非常に低かった(図8参照)。
d) 結論
0.1mg/kgにおいて、XG−102(配列番号11)は、好中球および全細胞の気管支肺胞腔内への動員を減少させ、TNFのレベルの減少傾向を増大させることが観察できた。さらに、組織スライドの本調査は、気管支の周辺空間において、炎症細胞の堆積が減少していることを示した。従って、XG−102(配列番号11)が、ブレオマイシン誘発性炎症を減少させたという結論付けが可能である。
グループ:ビヒクル、XG−102(配列番号11)0.001mg/kg、およびXG−102(配列番号11)0.1mg/kg
経路:s.c.経路、10日間で3回
a) 気管支肺胞洗浄空間への細胞動員
0.001mg/kgにおいて、XG−102(配列番号11)は、リンパ球動員を著しく低減させ、この時点ではリンパ球動員によって特徴付けられる炎症段階中に動員された細胞の総数を著しく低減させた。0.1mg/kgでは、XG−102(配列番号11)は、全く作用しなかった(グループ当たりn=5匹のマウス;*,p<0.05;**,p<0.001)(図9参照)。
3μmの肺の切片を、ヘマトキシリンおよびエオシンで染色した。BLM投与の10日後に、炎症細胞の堆積、繊維性の区域、肺構造の欠損を観察した。XG−102を低投与量(0.001mg/kg)で投与した後には、炎症細胞の堆積等のパラメータの減少が、観察されたが、高投与量(0.1mg/kg)で投与した後には観察されなかった(図10参照)。
0.001mg/kgの低投与量で3回にわたって投与されたXG−102(配列番号11)が、ブレオマイシン誘発性後炎症、特に、この時点で観察されるリンパ球動員を低減するという結論付けが可能である。さらに、当該投与量で3回にわたって投与された試験物質が、ブレオマイシン誘発性腺維症を弱毒化する。肺構造がより良好に保存された、ほとんど広がっていない繊維性の区域が、観察できた。
アルツハイマー病における、典型的な全てのDレトロ−インベルソIB(s)ペプチドXG−102(配列番号11)の活性を判定するために、ロンドン型変異およびスウェーデン型変異のAPP751を過剰発現するhAPP−遺伝子導入マウスモデルにおいて、XG−102(配列番号11)を、モリス水迷路の行動試験と、プラーク負荷を測定する免疫組織学的試験と、マウスの脳内のβ−アミロイド1-40およびβ−アミロイド1-42レベルを測定するELISA試験とを用いて評価した。
i) イントロダクション
本調査は、5ヶ月齢(±2週齢)の雌のhAPPTgマウスを用いて、試験物質(XG−102,配列番号11)の、行動マーカー、生化学的マーカー、および組織学的マーカーについての有効性を評価するためのものであった。このために、マウスを、4ヶ月間、2週間または3週間ごとに治療し、治療期間の終わりに、行動を、モリス水迷路において評価した。犠牲にしたマウスの、脳、CSF、および血液を採取した。Tgマウスの異なる4つの脳のホモジネート分画およびCSFにおいて、Aβ40およびAβ42のレベルを判定した。治療グループ当たり8匹のTg動物の皮質および海馬におけるプラーク負荷を、定量した。
C57BL/6xDBAのバックグランドを有する、5ヶ月齢(±2週齢)の雌のTgマウスを、治療グループ1〜3(n=12)にランダムに割当てた。動物に、ビヒクルまたは2つの異なる濃度のXG−102(配列番号11)を、生後5ヶ月から始まって4ヶ月間継続して、2週または3週ごとに皮下(s.c.)塗布して投与した。本調査に用いた全ての動物は、黒い目をしており、MWMプールの外の目印を知覚したと思われる。しかし、一匹の動物だけは視力が弱かった。これは、いわゆる予備試験である目に見えるプラットフォームのトレーニングにおいて確認されたことであった。治療開始前、予備を含む全ての動物を、調査のために隔離した。特定の動物の視覚障害が確認された場合、当該マウスは、本調査から除去される。
各マウスは、耳標によって識別される。これらのマウスは、個々の通気飼育カゴ(IVC)内の、Rettenmaier(登録商標)によって提供された標準的な齧歯類の寝具の上に収容された。各飼育カゴには、最大5匹のマウスが収容されている。マウスは、国際基準に基づいて記載されたJSW標準操作手順(SOP GEN011)に従って飼育した。各飼育カゴは、調査番号、性別、マウスの個体登録番号(IRN)、出生日、および、スクリーニング日、並びに、治療グループの割当てを示す色付きのカードで識別した。調査中の気温は、約24°Cに維持し、相対湿度は、約40〜70%に維持した。動物を、一定の明暗サイクル(12時間ごとの明/暗)下で収容した。動物は、自由に、通常の水道水を利用可能であった。
40匹の雌のhAPP遺伝子導入マウスを、異なる2つの投与量の試験物質XG−102(配列番号11)で、すなわち、2週間ごとに0.1mg/kg(b.w.)で、または、3週間ごとに10mg/kg(b.w.)で、治療するか(グループ当たりn=12)、または、4ヶ月にわたり3週間に1度、ビヒクル(n=12)(s.c.)で治療した。
モリス水迷路(MWM)試験を、直径100cmの黒い円形プールにおいて行った。温度が22±1°Cの水道水を充填し、プールを、視覚的に4つの区域に分割した。水の表面の真下約0.5cmに、透明のプラットフォーム(直径8cm)を置いた。予備試験を除く、全試験セッションの間、プラットフォームを、プールの南西の四分区間内に置いた。4日間続くトレーニングセッションの前日に、動物は、いわゆる「予備試験」(60秒続く試験を2回)を行って、各マウスの視覚能力が正常であるかを確認する必要があった。この条件を満たした動物だけを、MWM試験に用いた。
治療周期の終わり、且つ、全ての行動試験の後に、残った全てのマウス(n=28)を犠牲にした。このために、全てのマウスを、SOP MET030に記載される標準的な吸入麻酔(Isofluran, Baxter)によって沈静した。
各Tgマウスの4つの異なる脳ホモジネート分画、およびCSF試料における、Aβ1-40およびAβ1-42のレベルを、ELISA技術によって評価した。高感度のAβ1-40およびAβ1-42ELISA試験キットを、The Genetics Company(商標),スイス(SOP MET058)から購入した。
調査した全Tg動物の脳組織は、本手順のばらつきによる偏りを回避するために、正確に同じ方法で処理した。24Tgマウス(グループ当たり8匹)の脳の半分から、各層(全部で5層)当り、20cryo−切片を、10μmの厚さ(Leica CM 3050S)で矢状に切断し、5つ(各層から1つずつ)を処理し、プラーク負荷の定量化を評価した。矢状の5つの層は、Paxinos and Franklinの形態アトラス「The Mouse Brain」(第2版)に記載の、図104〜105、107〜108、111〜112、115〜116、および118〜119に対応している。
i) 行動
モリス水迷路試験では、スイミングプールの長さ、スイミング経路、逃避潜在時間、スイミング速度を、および、以前のプラットフォームを越えるプローブテストでは、各Tg動物について、位置、およびプールの各四分区間で過ごす時間を、特別なコンピュータソフトウェアで測定した。
全てのTgマウスの、CSF試料、および脳標本からの試料を、市販のAβ1-40およびAβ1-42ELISAで分析した。適切な基準の測定を同時に行った。脳標本からの試料2部を分析した。試料の数が少ないため、CSF試料は、1回の測定のみで分析した。
i1) アミロイド沈着およびプラーク負荷の測定
6E10免疫組織化学のために、次の評価手順を用いた。
i) 一般的観察
全部で40匹の雌のhAPP Tgマウスを、調査の対象とした。これらのマウスのうち、12匹の動物が、治療期間が終了する前に、原因不明により死亡した。
MWMにおける空間的学習は、XG−102(配列番号11)の治療によっては、全く影響されない状態で維持された。0.1mg/kgで治療したマウスは、1日目と4日目との間において、学習実績が悪いという傾向を示した。1日目および4日目の平均実績の二方向ANOVAにより、全てのグループ(p<0.001)にとって、有意の高い学習を示しただけでなく、因子処理の有意の影響(p=0.045)も示した。しかし、ボンフェローニのポストテストは、有意点まで達しなかった。
aa) 脳ホモジネート分画のAβレベル
試験化合物XG−102(配列番号11)による治療は、脳ホモジネートAβ1-40レベルに影響を与えなかった(図11参照)。Aβ1-42レベルのグループ間の差異は、トリトンX−100分画において現れただけであった。トリトンX−100分画では、低投与量の試験化合物XG−102(配列番号11)(0.1mg/kg)で治療された動物は、ビヒクルグループ(p<0.05)および高投与量のグループ(p<0.01)と比べて、著しい低下を示した。
試験物質XG−102(配列番号2)による治療の後、CSFのAβ1-40およびAβ1-42レベルは、ビヒクルグループと比べて、著しく低下した。どちらグループも、Aβ1-40およびAβ1-42のp値は、高投与量(10mg/kg)ではp<0.01であり、XG−102(配列番号2)の低投与量では<0.05であった(図12参照)。
aa) アミロイド沈着およびプラーク負荷
プラーク負荷を、異なる2つの方法によって定量化した。一方の方法である、主にヒトアミロイドペプチドのAA1−1に対する6E10を用いたIHC染色法を行った。他方の、成熟した神経炎プラークのベータ−シート構造およびコアを標識化するチオフラビンS染色法を行った。
・モリス水迷路において測定された空間的ナビゲーションは、治療から影響を受けない状態で維持された。0.1mg/kgのXG−102(配列番号11)の治療により、学習実績は、結果的に、トレーニングの第1日目と最終日との間で、わずかにより乏しくなった。
・これとは異なり、チオフラビンS染色法によって検出された海馬のベータ−シート負荷は、XG−102(配列番号11)の治療後、投与量に依存して低減し、低投与量である0.1 mg/kgのXG−102(配列番号11)において、大きく低減したが、残留した皮質のプラーク負荷は、不変のまま維持された。処理開始時における、年齢に依存した、海馬内のプラーク堆積の開始に従って、これは、プラーク堆積の初期の段階におけるベータ−シート形成に対する初期のアクションを示唆している。
実施例15は、2型糖尿病の治療において、IB(s)ペプチド、並びに、全てのDレトロ−インベルソIB(s)ペプチド、およびその改変体の活性を決定すること、特に、2型糖尿病のdb/dbマウスモデルにおけるXG−102(配列番号11)による慢性的治療の効果を、空腹時血糖値を3日ごとに(28日間)に測定することによって、判定することを、意図するものである。
i) 動物
全部で二十(20)匹の雄のdb/dbマウス(8週間齢)を、Charles River(ドイツ)から入手した。他の記載がない限り、到着後、動物は、グループごとに(グループ当たりn=6〜7)収容し、げっ歯類用の標準食(Altromin standard #1324 chow; C. Petersen, Ringsted,デンマーク)および水を、自由に与えた。
到着後、4日後において(On day-4)、マウスを、血糖値(空腹時;Biosen S line分析器(EKF diagnostic,ドイツ)上で測定した血糖)に基づいてランダム化して、次の薬剤治療グループ(n=6)のうちの1つに加えた。
2) XG−102(配列番号11)、1mg/kg、s.c.
3) XG−102(配列番号11)、10mg/kg、s.c
上記の全ての投与量は、ベースフリーで測定した。薬剤の純度:95.28%,ペプチド含有量:78.0%。全ての化合物を、3ml/kgの容積で、皮下(s.c.)投与した。ビヒクルコントロールおよびXG−102(配列番号11)の製剤説明は、次のとおりである。
・ 希釈した製剤の保存:室温で最大24時間
溶解する前に、粉末を、−20°Cで保存した。原液の安定性は、約−80°Cで3ヶ月である。動物に投与するための希釈した製剤の安定性は、室温で24時間である。未使用の希釈材料は、4〜8°Cで保存されているならば、最大7日間保存可能であった。
8日間の環境順化の後、マウスを、アウトライングループに従って、21日間、毎日午前8時に、午後4時の消灯の8時間前にSC投与することによって、治療した。その後、調査21日目に、最も高濃度のXG−102(配列番号2)(10mg/kg)の投与を停止し、その一方で、調査28日目まで、日用量のビヒクルコントロールおよびXG−102(配列番号2)(1mg/kg)を継続した。調査28日目から111日目の終了日まで、ビヒクルおよびXG−102(配列番号2)(10mg/kg)で治療されたマウスを、ウォッシュアウト期間(投与なし)において観察し、その一方で、XG−102(配列番号2)(1mg/kg)で治療したマウスを、28日間の治療後に、処分した。
投与の6時間後に、7時間の空腹状態の動物からの血糖を、尻尾の血管からの10μlの血液試料を、ヘマトクリットチューブに採取することによって測定し、次に、Biosen s-line分析器(EKF-diagnostic、ドイツ)で分析した。
グループ1+3:マウスを代謝飼育カゴの中に置いて、24時間の食料および飲料摂取、並びに、24時間の尿および糞の生成を記録した。マウスを、n=6〜7の2つのサブチームに分類し、続いて、調査71〜72日目に、代謝の特性付けを行った。
グループ1+3:3つのケース(調査57日目、66日目、および108日目)において、血液を、尻尾の血管から、EDTAが被覆されたヘマトクリットチューブ(100μl)を用いて採取した。その後、血液の遠心分離を行い、血漿を採取し、−20°Cで、測定まで保存した。その後、次のアジポキン/サイトカインのパネルを、Luminexに基づいた7つのplex、すなわち、レプチン、レジスチン、MCP−1、PAI−1、TNFα、インスリン、およびインターロイキン−6(IL−6)を用いて決定した。
グループ1+3(111日目):次の臓器、すなわち、鼠径部皮下脂肪、副睾丸脂肪、後腹膜脂肪、脳、肝臓、腎臓、脾臓、および心臓を抽出し、重量を量った。ここに記載の全ての臓器は、場合によっては行われる将来の組織病理学検査のための4%PFA中の試料である。また、膵臓(全体)を、場合によっては後に行う立体学的且つ免疫組織化学分析のために採取し、目を、場合によっては後に行う網膜症の分析のために採取した。グループ2(28日目):組織も血漿も採集しなかった。
i) 一般的観察
急性の投与周期の間、動物は、通常のレベルの敏捷さおよび活性を示しており、薬剤で治療した動物において、鎮静作用の徴候はなかった。ビヒクルで処理された動物間では、食料および飲料摂取は、通常の範囲内であった。
空腹時血糖値(絶対および相対)が、図15に示されている。グループAおよびCにおいて、空腹時血糖を、68日目まで3日ごとに測定し、111日目の終了日まで、定期的に測定した。
体重の測定(絶対および相対)が、図16に示されている。XG−102(配列番号2)(10mg/kg)で治療したマウスにおいて、体重増加が、ビヒクルコントロールと比べて、明らか且つ有意(p<0.001)に阻害されたことが観察された。この作用は、投与の28日目から現れ、終了日である111日目まで持続した。これとは異なり、低投与量のXG−102(配列番号2)(1mg/kg)では、投与した28日間の間、体重に何の作用も観察されなかった。
ビヒクルまたはXG−102(配列番号2)(10mg/kg)の、調査68目日の代謝飼育カゴにおいて、測定される、24時間の食料および飲料摂取、並びに、尿および糞の生成に与える影響が、図17(g)および図18(体重のgに標準化された)に示されている。XG−102(配列番号2)(10mg/kg)は、食料摂取および尿の生成を減少させる傾向があったが、ビヒクルコントロールと比べて、測定されたパラメータのいずれにも有意の作用も与えなかったことが、観察された。
57日目、77日目、および108日目に測定されたビヒクルまたはXG−102(配列番号2)(10mg/kg)が、インスリン、MCP−1、およびIL−6の血漿レベルに与える作用が、図19に示されており、tPAI−1、TNF、およびレジスチンの血漿レベルに与える作用が、図20に示されている。XG−102(配列番号2)で治療された動物の77日目および108日目において、血漿レジスチンのレベルが有意に高かったことを除いて、XG−102(配列番号2)(10mg/kg)は、ビヒクルコントロールと比べて、測定されたパラメータのいずれにも、有意の作用を与えなかったことが観察された。
ビヒクルまたはXG−102(配列番号2)(10mg/kg)の、副睾丸脂肪パッド、鼠径部皮下脂肪パッド、および後腹膜脂肪パッドの組織重量に与える作用が、図21に示されている。XG−102で治療されたマウスでは、ビヒクルコントロールと比べて、副睾丸(p<0.05)および後腹膜(p<0.01)の脂肪質量における著しい減少が、観察された。
以下に、本発明に係る幾つかの好ましい各実施形態を列挙する。
Claims (7)
- JNK阻害剤の、慢性閉塞性肺疾患(COPD)または肺腺維症を治療するための薬剤組成物を調製するための使用であって、
上記JNK阻害剤は、配列番号11に記載のアミノ酸配列から構成されているか、またはその改変体であり、
上記改変体は、配列番号11のアミノ酸の1〜2個の置換、付加、および/または、削除を含み、かつJNKを発現する細胞内に存在するときに、c−Jun、ATF2、およびElklから構成される群から選択されるJNK標的転写因子の少なくとも1つの活性化を阻害するものである、使用。 - 請求項1において規定されたJNK阻害剤をコードする、単離された核酸の、慢性閉塞性肺疾患(COPD)または肺腺維症を治療するための薬剤組成物を調製するための、使用。
- 請求項2において規定された核酸を含むベクターの、慢性閉塞性肺疾患(COPD)または肺腺維症を治療するための薬剤組成物を調製するための使用。
- 請求項3において規定されたベクターを含む細胞の、慢性閉塞性肺疾患(COPD)または肺腺維症を治療するための薬剤組成物を調製するための使用。
- 請求項1〜4のいずれか1項に係る使用であって、上記薬剤組成物は、非経口経路(静脈内経路、筋肉内経路、皮下経路、皮内経路、経皮経路を含む)、経腸経路(経口経路、直腸経路を含む)、局所経路(経鼻経路、鼻内経路を含む)、および、他の経路(表皮送達またはパッチ送達)から構成される群から選択された1つの投与経路によって投与される、使用。
- 請求項1〜5のいずれか1項に係る使用であって、上記JNK阻害剤の投与量(kg体重当たり)は、10mmol/kgまでの範囲内である、使用。
- 請求項1〜6のいずれか1項に係る使用であって、上記JNK阻害剤の投与量は、1pmol/kg〜1mmol/kgである、使用。
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Cited By (5)
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JP2015232008A (ja) * | 2008-05-30 | 2015-12-24 | ザイジェン インフラメイション リミテッド | Jnkシグナル伝達経路に対する、細胞透過性のペプチド性阻害剤の種々の、疾病を治療するための使用 |
US10967038B2 (en) | 2010-10-14 | 2021-04-06 | Xigen Inflammation Ltd. | Use of cell-permeable peptide inhibitors of the JNK signal transduction pathway for the treatment of chronic or non-chronic inflammatory eye diseases |
US10624948B2 (en) | 2013-06-26 | 2020-04-21 | Xigen Inflammation Ltd. | Use of cell-permeable peptide inhibitors of the JNK signal transduction pathway for the treatment of various diseases |
US11779628B2 (en) | 2013-06-26 | 2023-10-10 | Xigen Inflammation Ltd. | Use of cell-permeable peptide inhibitors of the JNK signal transduction pathway for the treatment of various diseases |
US11331364B2 (en) | 2014-06-26 | 2022-05-17 | Xigen Inflammation Ltd. | Use for JNK inhibitor molecules for treatment of various diseases |
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