JP2011509281A - 網膜神経節ニューロン変性を予防又は治療するためのビコイドファミリーのホメオタンパク質の使用 - Google Patents
網膜神経節ニューロン変性を予防又は治療するためのビコイドファミリーのホメオタンパク質の使用 Download PDFInfo
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Abstract
【選択図】なし
Description
概略的に、網膜は、ニューロンの3つの主な層を含む:光受容ニューロン(錐体及び杆体)、双極ニューロン及び神経節ニューロン。その他のニューロン、すなわちアマクリンニューロン及び水平ニューロンは、調節性の役割を演じる。光受容ニューロンは光に対して反応し、それらが生じた信号は、双極ニューロンにより、その軸索が視神経の神経線維を構成する神経節ニューロンに伝達され、情報が確実に脳に送られるようにする。
ホメオタンパク質又はホメオドメインタンパク質は、生物の形態形成に関与する細胞遊走及び分化の現象において主要な役割を演じる転写因子である。これらは、60アミノ酸の配列であるホメオタンパク質の存在を特徴とし、これは特徴的な構造(ヘリックス/ターン/ヘリックス)を有するDNA結合ドメインである。ショウジョウバエ(Drosophila)のアンテナペディアタンパク質の単離されたホメオドメインが、まず、培養ニューロンの膜を横切り、次いで、核に蓄積して神経突起の成長を促進することが示された(欧州特許出願第0485578号(Joliotら, Proc Natl Acad Sci USA, 88, 1864〜1868, 1991))。アンテナペディアホメオドメインの透過特性は、その3番目のヘリックスにより与えられ、ホメオタンパク質間で高度に保存されているようである。神経突起の成長に対するその特性は、コンセンサス配列ANNNNCATTAにより規定される結合部位のレベルにて、そのDNA結合特性と関連しているようである(欧州特許出願第0485578号(Joliotら, Proc Natl Acad Sci USA, 88, 1864〜1868, 1991))。
Otx2のこの新しい特性は、インビトロ培養における成体神経節ニューロンの生存を改善するため、及びインビボで神経節ニューロン変性を予防又は治療するためのその使用、及びより一般的にはビコイドファミリーのホメオタンパク質の使用、特にOtxサブファミリーの使用を提案することを可能にする。
本発明は、特に、いずれの光受容ニューロン変性も示さない患者に用いることができる。
ヒトOtx2ホメオタンパク質のアイソフォーム1(SwissProt P32243)をコードする配列を、イソプロピル-β-D-チオガラクトシド(IPTG)により誘導可能なtrcプロモーターの制御下で、プラスミドpTchTEV2 (NcoI-HindIIIセグメントを、rTEVプロテアーゼのための切断部位の上流でこれとフレーム内になり、その後のC末端の位置にmyc-his6タグが続くような、Otx2コード配列を含むPCR生成物の挿入を可能にするリンカーで置き換えて、プラスミドpTrOtx2hTevを作製することにより、プラスミドpTrcHis2 (Invitrogen)から導く)にクローニングした。pTrOtx2hTevにより発現される組換えタンパク質は、C末端位置でMycタグ及び6×Hisタグと融合されたOtx2配列を含む。これは、熱ショックにより形質転換された大腸菌(E. coli)株BL21 CodonPlus-RP (Novagen) plus RP"において生成された。寒天-LB-アンピシリンのペトリ皿上で37℃にて一晩の形質転換された細菌の選択の後に、組換えタンパク質の発現を、37℃での一晩のインキュベーションにより、自己誘導培養培地(IPTG様) OverNight Express Instant TB培地(Novagen)にて誘導する。遠心分離の後に細菌を氷上で溶解バッファー(バッファー:20 mM NaPO4、0.5 mM NaCl、プロテアーゼ阻害剤含有、EDTA非含有)中に、細菌ペレット1グラムあたり3mlのバッファーで採集し、1000 psiにてフレンチプレスに3回通すことにより溶菌する。溶菌物を遠心分離し、上清を回収し、0.45μmを通してろ過する。タンパク質を、0.1 M NiSO4とともに充填した1mlのHitrap Chelating HPカラム(Amersham)で精製し、上清を0.5 ml/分にて通過させる。10 mM、次いで50 mMのイミダゾールを含有するバッファーを用いて2回洗浄する。溶出を、250 mMのイミダゾールを含むバッファー1mlの10フラクションにより行う。最後の溶出を、1Mのイミダゾールを含むバッファーで行う。溶出フラグメントの純度は、SDS-PAGE電気泳動、次いでクーマシーブルーでの染色により確認した。
Otx2が最も豊富な3つのフラクションを合わせる。そのOtx2濃度は、およそ200μg/mlである。このようにして得られた調製物を、Tris 50 mM/EDTA 0.5 mM/NaCl 200 mMバッファーに対して透析し、45%グリセロールを含む同じバッファー中で-20℃にて貯蔵する。グリセロールは、培養培地に対する透析によりそれぞれの実験の前に除去する。
網膜細胞培養
タンパク質の影響を、分離及び培養の後の網膜ニューロンに対して試験した。2つのプロトコルを用いた。まず、全ての型の網膜細胞を含む混合培養、次いで、精製された神経節ニューロン培養。
用いたプロトコルは、Gaudinらにより記載されるものである(Invest Ophthalmol Vis Sci, 37, 2258〜2268, 1996)。
滅菌カバーガラスを、2μg/cm2のポリ-D-リジン(Sigma P-6407)で37℃にて一晩、次いで1μg/cm2のラミニン(Sigma L-2020)で37℃にて3時間、前処理する。網膜を、L-グルタミン非含有CO2-非依存性培地(Gibco 18045-054)中で解剖する。網膜を鋏で小片に切断し、0.6%グルコース及び0.5 mM EDTAを含むCa2+, Mg2+非含有PBS (Invitrogen 14190-185)ですすぎ、0.2%パパイン(Worthington Biochemicals, 10の網膜を含むチューブ中に1単位)の存在下で、37℃にて15分間インキュベートする。1.1 mMのEDTA、0.067 mMのβ-メルカプトエタノール及び5.5 mMのL-システインを含有するパパイン活性化溶液24μLに1単位のパパインを加えることにより、パパインを活性化した(37℃にて30分間)。加水分解を、DNアーゼI (Sigma, 5μg/ml)を加えた後に1mlの停止培地(Neurobasal A培地[Invitrogen 10888-022]及び10%胎児ウシ血清(FCS) [Invitrogen 10270-098])を加えることにより停止する。細胞を、すりガラスの(ground)パスツールピペットを用いて停止培地中で分離し、トリパンブルーを用いて計数して、死滅細胞を除き、種々の細胞密度で播種し(ウェルあたり75000〜400000細胞)、6日間培養で維持する。組換えOtx2タンパク質を透析し、培養培地で予備希釈し、細胞播種の直前に種々の濃度でウェルに分配する。無血清培養培地は、5μM L-グルタミン(Sigma G-6392)、2.5μM B27補体(Gibco 17504-044)、2.5μMグルタメート-アスパルテート(Gibco)、抗生物質/抗真菌剤(Gibco 15240-096)を補ったNeurobasal A培地(NBA) (Gibco 10888)で構成される。培養は、37℃にて、95%空気及び5% CO2のインキュベーター内で行う。培養6日目に、細胞を4%パラホルムアルデヒド(PAF)中で15分間固定し、次いで、PBSで3回すすぎ、免疫細胞化学を行うまで4℃にて貯蔵する。
用いたプロトコルは、Barresらにより記載されるものである(Neuron, 1, 791〜803, 1988)。
カバーガラスの前処理及び無血清培養培地は、混合培養についてと同じである。そうでないと記載しない限り、種々のインキュベーションは周囲温度にて行う。
網膜をD-PBS (Invitrogen 14287-080)中で解剖する。網膜をD-PBSですすぎ、次いで、パパイン(Worthington Biochemicals, 12の網膜を含有するチューブについて165単位)の存在下で37℃にて30分間インキュベートする。165単位のパパインを5mlのD-PBS及び1000単位のDNアーゼ(Sigma D4527)に加えることにより、パパインを37℃にて5分間活性化した。加水分解を、4mlの0.15%オボムコイドを加えることにより停止する。細胞を、すりガラスのパスツールピペットを用いて0.15%オボムコイド溶液中で、DNアーゼ及びウサギ抗ラットマクロファージ1次抗体(France Biochem AIA5 1240)の存在下で分離する。このようにして分離し、予備インキュベートした細胞懸濁物を遠心分離し、15 mlの0.02% BSA (Sigma A8806)含有D-PBS中に採集し、48tm Nitexフィルタ(Dutscher 074011)を通してろ過する。
網膜の解剖の前の一晩の期間に、「A」と命名する2つのペトリ皿(150 mm、Dutscher 35-1058)を、20 mlの50 mM Tris-HCl溶液、pH 9.5及び60μLのヤギ抗ウサギIgG 2次抗体(Interchim 111-005-003)とインキュベートし、「B」と命名する1つのペトリ皿(100 mm、Dutscher 35-1029)を、10 mlの50 mM Tris-HCl溶液、pH 9.5及び30μLのヤギ抗マウスIgM 2次抗体(Interchim 1 15-005-020)とインキュベートする。それぞれのパニング皿をPBSで3回洗浄する。皿を、次いで、D-PBS/0.2% BSAで飽和させる。B皿をマウス抗Thy1 IgM (T1 1D7, ECACCハイブリドーマ)と3時間インキュベートし、D-PBSで4回洗浄する。
ウサギ抗ラットマクロファージIgG 1次抗体と予備インキュベートした細胞懸濁物を、ヤギ抗ウサギIgG 2次抗体と、第1のA皿で36分間インキュベートする。非接着細胞を、33分間の第2インキュベーションのために第2のA皿に移す。
非接着細胞を、48 tm Nitexフィルタを通してろ過し、マウス抗Thy1 IgM 1次抗体を含むB皿にて45分間インキュベートする。次いで、B皿を数回(少なくとも10回)、D-PBSを用いて洗浄して、非接着細胞を累進的に除く。この累進は、顕微鏡下で監視する。
B皿を、37℃に予め加熱したアールの平衡塩溶液(EBSS) (Sigma E6267)を用いて2回すすぐ。B皿に接着した細胞を、4mlのEBSS及び200μLの2.5%トリプシン(Sigma T9201)を含有するトリプシン溶液と、37℃にて10分間インキュベートする。トリプシンを、4mlのD-PBS-30%胎児ウシ血清(FBS)溶液で不活性化する。細胞を、トリプシン-ブロッキング溶液と穏やかにピペット処理することにより剥離し、次いで遠心分離して計数する(トリパンブルーを用いる死滅細胞の排除)。
神経節ニューロンの生存に対するOtx2の影響を、文献において以前に記載された成体神経節ニューロン生存因子のものと比較した:混合網膜培養-馴化培地(Fuchsら, Invest Ophthalmol Vis Sci, 46, 2983〜2991, 2005)及びBDNF (脳由来神経栄養因子) (Johnsonら, J Neurosci, 6, 3031〜3038, 1986)。
Otx2及びBDNFを、培養培地中で50 ng/mlの濃度にて用いた。
混合網膜培養-馴化培地は、実施例2に記載したプロトコルに従って調製した混合培養物から調製する。最初の培養培地は、ミュラーグリア細胞の増殖を可能にするように10%のFCSを含む。細胞を、これらの条件下で集密まで培養する(およそ10日間)。NBAで4回洗浄した後に、培養培地を無血清の化学的に規定された培養培地(NBA+2% B27)にさらに2日間変更する。この馴化培地(CM)を回収し、遠心分離し、一定量に分け、液体窒素中で凍結させる。
上記の実験から、Otx2が、成体神経節ニューロンの新しい生存因子であり、その活性はBDNF又は馴化培地のものと同等又はそれより大きいことがわかる。
網膜神経節ニューロンの生存に対するOtx2の影響を、マウスモデルにおいてインビボで決定した。
選択したモデルは、N-メチル-D-アスパルテート(NMDA)中毒である。神経節ニューロンの生存を、神経節ニューロン、すなわちRGCにおいて特異的に網膜で発現される転写因子であるBrain 3A (Brn3A)の発現レベルを測定することにより決定した(Xiangら, J. Neurosci., 15, 4762〜4785, 1995)。
C57Bl6マウスの右目に、30 ngのOtx2又は1mMのNMDA又は3ng若しくは30 ngのOtx2を補った1mMのNMDAのいずれかを含む1μlの注射バッファー(PBS又は9‰NaCl)を与え、左目に、何も添加しない同じ容量の注射バッファーを与えた。
4日後に、動物を犠牲にし、網膜を回収し、そこからmRNAを抽出する。
結果を図4に示す。用いた添加物をX軸に沿って示す。右目と左目のBrn3A mRNAの量の比(HPRT mRNAに対して標準化)をY軸に沿って示す。
Claims (5)
- 網膜神経節ニューロン変性の予防又は治療のための医薬品を得るための、ビコイドファミリーのホメオタンパク質の使用。
- 前記網膜神経節ニューロン変性が緑内障において生じることを特徴とする請求項1に記載の使用。
- 培養網膜神経節ニューロンの生存を増大させるための、ビコイドファミリーのホメオタンパク質又は前記ホメオタンパク質を含む組成物の使用。
- 前記ホメオタンパク質がOtxサブファミリーに属することを特徴とする請求項1〜3のいずれか1項に記載の使用。
- 前記ホメオタンパク質がOtx2ホメオタンパク質であることを特徴とする請求項4に記載の使用。
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