JP6431480B2 - アルツハイマー病の治療および診断のためのビオチン複合体 - Google Patents
アルツハイマー病の治療および診断のためのビオチン複合体 Download PDFInfo
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- JP6431480B2 JP6431480B2 JP2015530100A JP2015530100A JP6431480B2 JP 6431480 B2 JP6431480 B2 JP 6431480B2 JP 2015530100 A JP2015530100 A JP 2015530100A JP 2015530100 A JP2015530100 A JP 2015530100A JP 6431480 B2 JP6431480 B2 JP 6431480B2
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Description
ある実施形態においては、本発明は、ビオチン部分とsiRNA部分とから実質的になる組成物に関する。
本発明の組成物
一般に、本発明は、リンカーの存在下または非存在下でビオチンとsiRNA配列とを含む新規組成物に関する。ある実施形態においては、該組成物はビオチン部分とsiRNA部分とから実質的になる。本明細書中で用いる「siRNA」は、有害なインターフェロン応答をヒト細胞において誘導しない、RISC(RNAi誘発性サイレンシング複合体)内に進入しうる二本鎖RNAまたは一本鎖RNAを意味し、例えば、それは、60個未満、好ましくは50個未満、40個未満または30個未満のヌクレオチドペアの二本鎖領域を有する。該siRNAまたはその切断産物は、例えば、標的RNA、好ましくは内因性または病原体標的RNAに対するRNAiを誘発することにより、標的遺伝子をダウンレギュレーションしうる。siRNAはタンパク質産生をサイレンシングすることが知られている。
本発明の1つの態様は、前記組成物のいずれかの治療的有効量を哺乳動物に投与する工程を含む、哺乳動物におけるアルツハイマー病の治療方法に関する。
もう1つの態様においては、本発明は、1以上の医薬上許容される担体(添加剤)および/または希釈剤と共に製剤化された前記のビオチン化組成物の1以上の治療的有効量を含む医薬上許容される組成物を提供する。後記に詳細に記載されているとおり、本発明の医薬組成物は、以下のものを包含する固体または液体形態での投与のために特別に製剤化されうる:(1)経口投与に適合化されたもの、例えば飲薬(水性または非水性溶液または懸濁液)、錠剤、例えば頬側、舌下および全身吸収を意図したもの、ボーラス、散剤、顆粒剤、舌への適用のためのペースト剤;(2)非経口投与に適合化されたもの、例えば皮下、筋肉内、静脈内または硬膜外注射によるもの、例えば無菌溶液もしくは懸濁液、または徐放製剤;(3)局所適用に適合化されたもの、例えばクリーム剤、軟膏剤または制御放出パッチまたはスプレー剤(皮膚に適用されるもの);(4)膣内または直腸内投与に適合化されたもの、例えばペッサリー、クリーム剤または泡剤;(5)舌下投与に適合化されたもの;(6)眼投与に適合化されたもの;(7)経皮投与に適合化されたもの;あるいは(8)鼻腔内投与に適合化されたもの。
ある実施形態においては、本発明は、アルツハイマー病を治療またはイメージングするためのキットに関する。例えば、キットは、前記の1以上のビオチン化組成物、および所望により、それらの使用のための説明を含みうる。更に他の実施形態においては、本発明は、1以上の医薬組成物もしくは診断用組成物、および/またはそのような組成物の投与を行うための1以上の装置を含むキットを提供する。例えば、本キットは、医薬組成物または診断用組成物と、直接注射を行うためのカテーテルとを含みうる。
5’−ビオチン−CUUACGCUGAGUACUUCGAUU−Dy547−3’
5’−Dy547−CUUACGCUGAGUACUUCGAUU−ビオチン−3’
5’−ビオチン−UCGAAGUACUCAGCGUSAGUU−Dy547−3’
該ビオチン−siRNA組成物を50nMで加え、4時間培養し、ついで20μlのFBSを加えて、培養を40時間継続した。ウェルをPBSで洗浄し、核対比染色剤としてのヘキスト(Hoechest)(1μg/ml)と共にインキュベートした。Dy547(赤)、ヘキスト(Hoechst)(青)および位相差のイメージを、Openlabイメージングソフトウェアにより制御される蛍光顕微鏡を使用して捕捉し、それは3つのイメージを合体させた。該蛍光研究からの2つの最良のsiRNAに関して生物発光をアッセイした。A549Luc細胞を96ウェルプレートの1ウェル当たり5,000細胞でプレーティングした。該siRNAを5、50および250nMで無血清培地(50μl/ウェル)中で4時間インキュベートし、ついで通常の培地(D’MEM中の10% FBS)を加えて200μlにし、2日間培養した。細胞を新鮮培地で洗浄し、ルシフェリンを0.5mg/mlで加えた。M5プレートリーダー(Molecular Devices)を使用して発光を読取った。アッセイを3回重複して行い、平均値をプロットした。図4〜7を参照されたい。
本発明者らは、本発明において、ヒトタウタンパク質の突然変異発現および有害発現をノックダウンするためのsiRNA干渉技術を示唆し、それに取り組んだ。このために、本発明者らは、タウ遺伝子においてヒトP301S突然変異を発現するトランスジェニックマウスモデルを特徴づけした。Allen,B.ら,J Neurosci 22,9340−51(2002)。このモデルはタウ凝集、および特に運動行動における、以下の重篤な行動障害を示す。該症状は成体初期においては微々たるものであり有意なものではないが、自発的後脚立行動のような試験において捕捉されうる(図1A)。この行動はこのモデルにおいては数か月を経るにつれて徐々に低減し、3月齢における成体初期と比較して6月齢で有意になる。5〜6カ月後、該動物は特に後肢における麻痺の重篤な徴候をも示す。これらの行動は視覚的に観察され、歩行距離を測定する行動試験(開放野外条件中;図1B)および回転棒上で費やす時間を測定する行動試験(ロータロッド試験;図1C)において容易に捕捉されうる。これらのデータは該モデルに関する重要な情報を提供し、どのような試験形態を用いるべきか、およびタウタンパク質のsiRNA干渉のような治療戦略の有意な行動的効果がどの時点で評価されうるかに関する重要な情報を提供する。
shRNAプラスミド構築
2つのプライマー、すなわち、フォワード:5’−CAGGACTAGTCTTTTAGGTCAAAAAGAAGAAGCTTTGTAACCGTTGGTTTCCGTAGTGTA−3’(配列番号9)およびリバース:5’−TTCGAACCGGGGACCTTTCGCGTGTTAGGCGAACGTGATAACCACTACACTACGGAA ACCAAC−3’(配列番号10)をアニールさせ、該プライマーをPCRにより伸長させ、TOPO TAクローニングキット(Invitrogen Life Technologies,Carlsbad,CA)を使用してそれらをpCR2.1−TOPOベクター内にクローニングすることにより、tRNA−バリンプロモーターを構築した。鋳型としての該Topo TAベクター内の得られたtRNA−バリンプロモーター、前記フォワードプライマーおよび後記リバースプライマーを使用して、頭部−尾部の21bpのshRNA断片をPCR増幅した。ついで各shRNA断片をpCR2.1−TOPOベクター内にクローニングした。tRNA−バリン駆動性shRNAの生成のために使用したリバースプライマーは以下のとおりである。
AAAAAAATGAACTTCCCCGTCAGCTTGCAAGCTTCCAAGCTGACGGGGAAGTTCATCTTCGAACCGGGGACCTTTCG(配列番号11)。
AAAAAAGTGGCCAGGTGGAAGTAAAATCCAAGCTTCGATTTTACTTCCACCTGGCCACCTTCG AACCGGGGACCTTTCG(配列番号12)。
AAAAAAGGTGGCCAGATGGAAGTAAACCAAGCTTCGTTTACTTCCATCTGGCCACCCTTCGAACCGGGGACCTTTCG(配列番号13)。
AAAAAATGAAGTGAAGATGGATGCAGCCAAGCTTCGCTGCATCCATCTTCACTTCACTTCGA ACCGGGGACCTTTCG(配列番号14)。
AAAAAATGAAGTGAATCTGGATGCAGCCAAGCTTCGCTGCATCCAGATTCACTTCACTTCGA ACCGGGGACCTTTCG(配列番号15)。
Cos−7およびHeLa細胞の培養方法は既に記載されている。プラスミドおよびsiRNAを、70〜90%のコンフルエンシーでプレーティングされた細胞を含有する12ウェルプレートにおいて、リポフェクタミン・プラス(Lipofectamine Plus)(Invitrogen)で一過性にトランスフェクトした。注記されている場合を除き、5:1の比のsiRNAと発現プラスミドとを細胞内にトランスフェクトし、一方、tRNA−バリンshRNA実験では、10:1の比のshRNAプラスミドと発現プラスミドとを使用した。これらの条件下、ランダムフィールドにおける蛍光生細胞の視覚的計数によれば、トランスフェクション効率は50〜70%の範囲である(データ非表示)。
GFPおよびタウ構築物を発現するCos−7細胞からのライセートをトランスフェクションの24時間後に集め、一方、APPおよびAPPsw発現細胞ライセートを48時間の時点で集めた。内因性ラミンを発現するHeLa細胞からのライセートを抗ラミンsiRNAのトランスフェクションの後の72時間の時点で集めた。既に報告されているとおりにウエスタンブロットによりライセートを分析した。GFPおよびラミンをそれぞれ抗GFPマウスモノクローナル抗体(1:1000希釈;Medical and Biological Laboratories,Naka−ku Nagoya,Japan)および抗ラミンヤギポリクローナル抗体(1:25希釈;Santa Cruz Biotechnology,Santa Cruz,CA)で検出した。この研究において使用した追加的抗体には、抗タウマウスモノクローナル抗体(1:500希釈)(Calbiochem,San Diego,CA)、22C11抗APPマウスモノクローナル抗体(1:500希釈)(Chemicon International,Temecula,CA)、およびローディング対照としての、α−チューブリンに対するマウスモノクローナル抗体(1:20 000希釈)(Sigma,St Louis,MO)が含まれる。二次抗体はペルオキシダーゼ共役ロバ抗ヤギまたはペルオキシダーゼ共役ロバ抗マウス(1:15 000希釈)(Jackson ImmunoResearch Laboratories,West Grove,PA)であった。
関心のある遺伝子に対するsiRNAを作製するための効率的方法は、T7 RNAポリメラーゼを使用するインビトロ転写反応において、標的遺伝子に相補的な短いRNA二本鎖を製造することである。しかし、T7ポリメラーゼのためのプライミング要件は、Gが、転写を開始させるプライミングヌクレオチドであることを要求する。これは、対応するインビトロ転写RNA二本鎖が産生されうる標的遺伝子におけるヌクレオチド位置を限定する。T7 RNAポリメラーゼにより課されるこの制限を克服するために、本発明者らは、5’末端に非相補的Gヌクレオチドを含有するsiRNAを設計した。生じたsiRNAは、該標的に対する単一の5’ミスマッチを伴うアンチセンス鎖上の20個の相補的ヌクレオチドを含有する。開始Gのこの含有は、原理上は、標的遺伝子の任意の20ヌクレオチド断片に対してdsRNAがインビトロで産生されることを可能にするはずである。
RNAiはヒト疾患に対する潜在的治療としての有望さを保持している。しかし、遺伝子特異的または対立遺伝子特異的siRNAを成功裏に開発する場合の課題は、所望のサイレンシング特性を有するsiRNAの選択および設計である。転写産物の種々の領域に標的化される個々のsiRNAは、しばしば、効力および特異性における顕著な相違を示す。典型的に、幾つかの標的部位および設計は、最適サイレンシングが達成される前に試験される必要がある。本明細書において、本発明者らは、化学合成siRNA二本鎖の時間およびコストの欠点を回避するだけでなく、T7ポリメラーゼでのインビトロ転写により課される配列制限を除去する簡便な方法を記載している。
本明細書中で挙げられている全ての刊行物および特許(後記に挙げられているものを含む)の全体を、各個の刊行物または特許が参照により本明細書に組み入れられると具体的かつ個別に示されている場合と同様に、参照により本明細書に組み入れることとする。矛盾が生じる場合には、本明細書におけるあらゆる定義を含む本出願が優先する。
本発明は、とりわけ、siRNAを含むビオチン化組成物を提供する。本発明の特定の実施形態が記載されているが、前記明細書は例示的であり、限定的ではない。本明細書を精査すれば、本発明の多数の変更が当業者に明らかとなるであろう。
Claims (14)
- siRNA部分にコンジュゲートしたビオチン部分を含む組成物であって、
前記組成物が、抗体、抗原、アビジン又はストレプトアビジンを含まず、
前記siRNA部分が、配列番号1のヌクレオチド又は配列番号1に対して少なくとも90%の配列相同性を有する核酸を含み、
前記組成物が、アミロイド前駆体タンパク質をコードする遺伝子を部分的、実質的又は完全に欠失させ、サイレンシングし、不活性化し、妨害し、又はダウンレギュレーションする、組成物。 - 組成物が、siRNAとビオチンとの間のリンカーを更に含む、請求項1に記載の組成物。
- 診断剤を更に含む、請求項1又は2に記載の組成物。
- 診断剤が、発蛍光団、発色団、化学発光剤、放射性核種、不対スピン原子、フリーラジカル及び造影剤からなる群から選択される、請求項3に記載の組成物。
- ビオチン部分及びsiRNA部分からなる、請求項1に記載の組成物。
- siRNA部分が、5’末端にグアノシンを含む、請求項1〜5のいずれか1項に記載の組成物。
- siRNA部分のセンス又はアンチセンス鎖が、30、25、24、23、22、21、20、19、18又は17ヌクレオチド長以下である、請求項1〜6のいずれか1項に記載の組成物。
- 請求項1〜7のいずれか1項に記載の組成物の治療的有効量と、薬理学的に許容される担体又は希釈剤とを含む、薬理学的に許容される製剤であって、抗体、抗原、アビジン又はストレプトアビジンを含まない、製剤。
- 請求項1〜7のいずれか1項に記載の組成物の治療的有効量を含む、哺乳動物におけるアルツハイマー病の治療のための医薬組成物であって、抗体、抗原、アビジン又はストレプトアビジンを含まない、医薬組成物。
- 哺乳動物がヒトである、請求項9に記載の医薬組成物。
- 請求項3又は請求項4に記載の組成物の検出可能な量を含む、対象のイメージを生成するための組成物。
- 対象がヒトである、請求項11に記載の組成物。
- 哺乳動物におけるアルツハイマー病の治療のための医薬の製造における、請求項1〜7のいずれか1項に記載の組成物の使用。
- 対象のイメージを生成するための組成物の製造における、請求項3又は4に記載の組成物の使用。
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US9655977B2 (en) | 2017-05-23 |
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EP3441467A2 (en) | 2019-02-13 |
JP2019059735A (ja) | 2019-04-18 |
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EP3441467A3 (en) | 2019-04-24 |
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US20150246134A1 (en) | 2015-09-03 |
EP2890788A1 (en) | 2015-07-08 |
AU2013308519A1 (en) | 2015-04-09 |
US20170326244A1 (en) | 2017-11-16 |
AU2021250967A1 (en) | 2021-11-11 |
CA2883130A1 (en) | 2014-03-06 |
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