JP2006521815A - Smad7に対するアンチセンスオリゴヌクレオチド(ODN)及びその医療分野での使用 - Google Patents
Smad7に対するアンチセンスオリゴヌクレオチド(ODN)及びその医療分野での使用 Download PDFInfo
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- JP2006521815A JP2006521815A JP2006507636A JP2006507636A JP2006521815A JP 2006521815 A JP2006521815 A JP 2006521815A JP 2006507636 A JP2006507636 A JP 2006507636A JP 2006507636 A JP2006507636 A JP 2006507636A JP 2006521815 A JP2006521815 A JP 2006521815A
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Abstract
Description
5’−GTXYCCCCTTCTCCCXYCAG−3’
(上式中、Xは、シトシンと5−メチルシトシンと2’−O−メチルシトシンからなる群から選択される窒素性塩基を含むヌクレオチドであり、Yは、グアニンと5−メチルグアニンと2’−O−グアニンからなる群から選択される窒素性塩基を含むヌクレオチドであり、但し、ヌクレオチドX又はYの少なくとも1つは、メチル化窒素性塩基を含む);
又はそれに対する相補配列を含むアンチセンスオリゴヌクレオチドホスホロチオエートである。
5’−GTXGCCCCTTCTCCCXGCAG−3’
(上式中、Xは、5−メチル2’−デオキシシチジン5’−モノホスフェートである)
を有するアンチセンスオリゴヌクレオチドで代表される。
5’−ZTXGCCCCTTCTCCCXGCAZ−3’
(上式中、Xは、5−メチル2’−デオキシシチジン5’−モノホスフェートであり、Zは、2’−デオキシグアノシンメチルホスホネートである)
を有するアンチセンスオリゴヌクレオチドで代表される。
5’−ZTXGCCCCTTCTCCCXGCAZC−3’
(上式中、Xは、5−メチル2’−デオキシシチジン5’−モノホスフェートであり、Zは、2’−デオキシグアノシンメチルホスホネートである)
を有するアンチセンスオリゴヌクレオチドである。
アンチセンスODNの合成
全てのSmad7アンチセンスODNは、標準ホスホロアミダイト化学プロトコル(Lesiak K.ら、1993年;Xiao W.ら、1996年)を用いた自動DNAシンセサイザーを使った標準自動手法を採用してMWG Biotech AG(MWG Biotech S.r.l.、フィレンツェ(Florence))によって合成した。
アポトーシスは、ヨウ化プロピジウム(PI)染色に続くフローサイトメトリーで解析した。
LPMCをホモジナイズして、全タンパク質を、10mM Hepes(pH7.9)、10mM KCl、0.1mM EDTA及び0.2mM EGTAを含有する緩衝液A中で抽出した。緩衝液に、1mMジチオスレイトール(DTT)、10μg/mlアプロチニン、10μg/mlロイペプチン及び1mMフェニルメタンスルホニルフルオライド(全ての試薬はSigma−Aldrichから)を補充した。
患者の外科的検体から取った粘膜外植片を、Smad7アンチセンスODN(配列番号4、配列番号5、両方とも最終濃度10μg/mlで用いた)の存在及び非存在下で40時間培養した。
様々な実験において得られた結果は、どのようにTGF−β1が、正常な被験者の腸から単離されたTリンパ球のアポトーシスを用量依存的に増大させたかを示す。
全てのSmad7アンチセンス及びセンスODNは、先に記述した標準的手法を使ってMWG Biotech S.r.i.(フィレンツェ)によって合成した。
5から6週齢オスSJL/Jマウスを特定病原体除去動物施設で保育した。大腸炎の誘導のために、3,5Fカテーテルを通じて、50%エタノール中の2.5mgのTNBS(pH1.5〜2.0、Sigma Aldrich)を直腸に投与してマウスを軽く麻酔した。カテーテルの先端を肛門縁から4cm中へ挿入して、100mlの流体(TNBS/エタノール)を結腸にゆっくりと滴下注入した。
指し示された死亡の時刻にマウスから取り出した組織を、10%ホルマリン溶液(Sigma Aldrich)で固定し、パラフィンに包埋して、組織切片に切り、ヘマトシリンとエオシンで染色した。染色した切片を、リンパ球浸潤、陰窩の伸長及び又は歪み、明白な潰瘍形成、及び腸壁の肥厚の存在のような様々な判断基準を用いて大腸炎の証拠に関して調査した。
0: 炎症の証拠無し。
1: 強拡大視野(hpf=強拡大視野)の<10%で浸潤が見られる低レベルのリンパ球浸潤であり、構造的変化は観察されない。
2: hpfの<10〜25%で浸潤が見られる中程度のリンパ球浸潤であり、陰窩伸長、粘膜層を越えて広がってはいない腸壁肥厚。
3: hpfの<25〜50%で浸潤が見られる高レベルのリンパ球浸潤であり、粘膜層を越えて広がる腸壁の肥厚。
4: hpfの>50%で浸潤が見られる顕著な程度のリンパ球浸潤であり、高い血管密度、歪みのある陰窩伸長、潰瘍形成のある全層性腸壁肥厚。
粘膜固有層単核細胞(LPMC)を結腸検体から単離した。該検体をまず、カルシウムマグネシウム除去のHBSS(Hanksの平衡塩類溶液、Sigma−Aldrich)で洗い、0.5cm片に切った。そして、それらを2回インキュベートした。各回は、EDTA(0.37mg/ml)とジチオスレイトール(0.145mg/ml)とを含有するHBSS中において37℃で15分間であった。その後、該組織を、37℃の震盪インキュベータで、コラゲナーゼDを含有するRPMI(400U/ml、Boehringer Mannheim Biochemicals、インディアナ州インディアナポリス)とDNアーゼI(0.01mg/ml、Boehringer Mannheim Biochemicals、インディアナ州インディアナポリス)中で消化した。
TNBSによる処置の2日後に、マウスの直腸に各Smad7アンチセンス又はセンスオリゴヌクレオチド150gを投与した。グループ毎に少なくとも5匹のマウスを調べた。5日目に、マウスを犠牲にして、腸全体の粘膜試料を取り、ウエスタンブロッティングでSmad7及びSmad3の含有に関して解析した。加えて、腸粘膜炎症程度実体を評価した。
粘膜固有層単核細胞と全結腸検体の両方を、上記手順を用いてホモジナイズした。そして、Smad7発現をウエスタンブロッティングで明らかにした。
活性TGF−β1の量を腸粘膜試料において測定した。この趣旨のために、上記に指し示したTNBS誘導大腸炎に罹患した又は罹患していないマウスからの粘膜試料から全タンパク質を抽出した。活性TGF−β1のレベルを、商業的入手可能なELISAキット(R&D Systems、Space Import−Export Sri、ミラノ)を用いて解析した。光学濃度を、Dynatech MR 5000ELISAリーダーで、波長490nmで測った。データは、pg/全タンパク質100μgで表した。
TNBSを受けた後で、マウスは、大腸炎の誘導の証拠によって下痢と体重減少を示した。その結腸は肉眼的にも大きくなり、その粘膜の組織学的な解析は、中程度から重度の炎症性病変を示した。
Claims (16)
- 下記の配列(配列番号2):
5’−GTXYCCCCTTCTCCCXYCAG−3’
(上式中、Xは、シトシン、5−メチルシトシン及び2’−O−メチルシトシンからなる群から選択される窒素性塩基を含むヌクレオチドであり、Yは、グアニン、5−メチルグアニンe2’−O−メチルグアニンからなる群から選択される窒素性塩基を含むヌクレオチドであり、但し、ヌクレオチドX又はYの少なくとも1つは、メチル化窒素性塩基を含む)又はそれに対する相補配列の少なくとも10ヌクレオチドの部分を含む21ヌクレオチド長までのSmad7に対するアンチセンスオリゴヌクレオチドホスホロチオエート。 - 前記配列の少なくとも1つのヌクレオチドがメチルホスホネートである請求項1記載のアンチセンスオリゴヌクレオチド。
- 前記少なくとも1つのメチルホスホネートヌクレオチドが、3’又は5’末端の一方のみ又は3’及び5’末端の両方に、或いは前記アンチセンスオリゴヌクレオチド配列に沿って位置している請求項2記載のアンチセンスオリゴヌクレオチド。
- 前記メチルホスホネートヌクレオチドがYである請求項2記載のアンチセンスオリゴヌクレオチド。
- 前記メチルホスホネートヌクレオチドがXである請求項2記載のアンチセンスオリゴヌクレオチド。
- 前記配列の少なくとも1つのヌクレオチドが、2’−O−メチルリボヌクレオチド5’−モノホスフェートである請求項1記載のアンチセンスオリゴヌクレオチド。
- 前記少なくとも1つの2’−O−メチルリボヌクレオチド5’−モノホスフェートが、3’又は5’末端の一方のみに、又は3’及び5’末端の両方に、又は前記オリゴヌクレオチド配列に沿って位置している請求項6記載のアンチセンスオリゴヌクレオチド。
- 2’−デオキシリボヌクレオチドが、対応するリボヌクレオチドで置き換えられている請求項1〜7のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 配列(配列番号4):
5’−ZTXGCCCCTTCTCCCXGCAZ−3’
(上式中、Xは5−メチル2’−デオキシシチジン5’−モノホスフェートであり、Zは2’−デオキシグアノシンメチルホスホネートである)
を有する請求項1〜8のいずれか一項に記載のアンチセンスオリゴヌクレオチド。 - 配列(配列番号15):
5’−ZTXGCCCCTTCTCCCXGCAZC−3’
(上式中、Xは5−メチル2’−デオキシシチジン5’−モノホスフェートであり、Zは2’−デオキシグアノシンメチルホスホネートである)
を有する請求項1〜8のいずれか一項に記載のアンチセンスオリゴヌクレオチド。 - 配列(配列番号3):
5’−GTXGCCCCTTCTCCCXGCAG−3’
(上式中、Xは5−メチル2’−デオキシシチジン5’−モノホスフェートである)
を有する請求項1記載のアンチセンスオリゴヌクレオチド。 - 医療分野での使用のための請求項1〜11のいずれか一項に記載のアンチセンスオリゴヌクレオチド。
- 1種又は複数の医薬的に許容されるアジュバント及び/又は賦形剤とともに、請求項1〜11のいずれか一項に記載のアンチセンスオリゴヌクレオチドの少なくとも1つを有効成分として含む医薬組成物。
- Smad7発現に関連する病態の治療用製剤の製造のための、請求項1〜11のいずれか一項に記載のアンチセンスオリゴヌクレオチドの使用。
- 前記Smad7発現に関連する病態が慢性炎症性疾患である請求項14記載の使用。
- 前記慢性炎症性疾患がクローン病及び潰瘍性大腸炎である請求項15記載の使用。
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