JP2016514155A - Abca1発現の音響化学誘導およびそのための組成物 - Google Patents
Abca1発現の音響化学誘導およびそのための組成物 Download PDFInfo
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Abstract
Description
本願の生物学的配列情報は、2013年9月10日に作成され、44617バイトのファイルサイズを有し、ファイル名"SG-2-SEQ-4_ST25.txt"を有するASCIIテキストファイル(参照により本願に組み込まれる)に含まれる。
雄のスプラーグ・ドーリー・ラット(180〜250g)は、Charles River Laboratories(ウィルミントン、マサチューセッツ州)から購入した。すべての動物実験は、AAALAC、USDAおよびOLAWの公認施設において行った。ラットは、滅菌ケージ(Alternative Design Manufacturing & Supply社、シロアムスプリングス、アーカンソー州)内に収容し、標準的な市販飼料(Lab Diet; Purina Mills社、セントルイス、ミズーリ州)および水には自由にアクセスさせた。動物は、12時間/12時間明暗サイクル、調節された温度(おおよそ24℃)および調節された湿度(おおよそ40%)中で飼育した。
ヒトapoE肝臓制御領域(HCR)、ヒトユビキチンCプロモーターおよび第1イントロンを含む発現ベクターpMIR0125(Mirus Bio社、マディソン、ウィスコンシン州)に804bpのヒトapoA1 PCR cDNA産物をサブクローニングしてapoA1発現プラスミドを構築した。最終構築物、pMIR0332-HCRUbC-h apoA1を配列決定した。得られたクローンは、報告されているヒトapoA1配列と一致した。ABCA1発現ベクターは、Origene社(ABCA1(NM 005502)Human cDNA ORF Clone、カタログ番号RC221861)から購入した。図1は、このベクターのオープンリーディングフレームにコードされるABCA1のアミノ酸配列(配列番号1)を示す。図2は、このベクターのABCA1オープンリーディングフレームのヌクレオチド配列(配列番号2)を示す。図3は、この全ベクターのヌクレオチド配列(配列番号3)を示す。図4は、ABCA1プラスミドの概略マップを示す。
これらのプラスミド(すなわちapoA1プラスミド、ABCA1プラスミドまたはapoA1およびABCA1プラスミドの組み合わせ)と市販の注射用OPTISONマイクロスフェア懸濁液とを混合した。麻酔剤:酸素と1.5〜3.0%イソフルランの吸入ガス混合物。加温用ベッドでラットの体温を37℃に維持した。26GA3/4インチカテーテルを用いて尾静脈注射を行った。混合物:OPTISONマイクロスフェア約1mLと、個々のプラスミドに用いたのと1mL当たり同じ濃度の(1)apoA1DNAプラスミド(1mL中おおよそ8mg)、または(2)ABCA1プラスミド(1mL中おおよそ7.3mg)、または(3)apoA1とABCA1プラスミドの組み合わせと混合した。
すべての肝臓超音波処理には、3S超音波プローブを備えたVIVID Iブランドイメージングシステム(GE Healthcare Systems社、ミルウォーキー、ウィスコンシン州)を用いた。すべての音響エネルギー設定は、診断用途の概略を述べたFDAガイドライン(ALARA原則)の範囲内であった。肝臓脈管構造および実質内のOPTISON混合物の外観を確かめるために、外部超音波を用いてラット肝臓を継続的に可視化した。イメージングには、低いメカニカルインデックス(MI)超音波音響エネルギー(例えば<0.4MI)を用い、治療には高めのMI(約1.3MI以上)を用いた。外科的に腹部を切除することはこれまでには行わず、肝臓を視覚化するためには外部超音波を用いた。表面の毛を除去するために、腹部の毛を剃った。
治療前に、各ラットに関してベースライン血清HDL-cを確認するために、6日間にわたって3つの尾静脈血液試料(0.5ml)を採取した。OPTISONマイクロスフェア懸濁液中のプラスミドでの治療後に、血液試料を毎日3日間採取し、次いで3日間の中断をおいて採取した。すべての血液試料は、リチウムヘパリン抗凝固薬を含むガラス試験管内に採取した。HDL値を定量するために、各血清試料を、臨床脂質パネルテストストリップ(clinical lipid panel test strip)(PTS #1710 Lipid Panel Test for CARDIOCHEK PA CHOLESTEROL ANALYZER、Polymer Technology Systems社、インディアナポリス、インディアナ州)を用いて分析した。グラフデータは平均+1SEMで示し、統計的有意性は2標本t検定で決定した。帰無仮説はP<0.05で棄却し、すべての統計解析はMINITAB12(Minitab社、ステートカレッジ、ペンシルベニア州、米国)を用いて行った。
図5は、ベースライン濃度および治療3日後の濃度を含む、治療ラットの血中HDL-c濃度のグラフを示す。本明細書に記載のソノポレーションによるABCA1の選択的肝臓形質導入は、ベースラインHDL-c濃度に対して血中HDL-cを増加させた。肝臓の超音波処理と組み合わせたABCA1プラスミドおよび音響化学的に活性なマイクロスフェア組成物での単一音響化学治療によって、HDL-cの15%の増加が生じた。本研究における驚くべき発見は、同じ超音波処理条件下でのapoA1プラスミドまたはABCA1およびapoA1プラスミドの組み合わせでの治療に対して、ABCA1プラスミド治療がHDL-cの優れた増加をもたらしたことである。
Claims (28)
- 細胞をトランスフェクトするのに有用な組成物であって、前記組成物が、活性型のATP結合カセットトランスポーターA1(ABCA1)をコードするプラスミドベクターと、音響化学的に活性なマイクロスフェアとの混合物を、薬学的に許容される水性担体中に含み、前記ベクターが、前記活性型のABCA1をコードする発現可能なオープンリーディングフレームと、哺乳動物細胞内で前記オープンリーディングフレームの発現を促進するように適合された少なくとも1つの配列とを含み、前記音響化学的に活性なマイクロスフェアが、タンパク質、脂質またはそれらの組み合わせを含むシェルに封入されたガス気泡を含み、前記マイクロスフェアは超音波音響エネルギーへの暴露によって崩壊可能であり、崩壊して前記封入されたガス気泡を放出するものである、前記組成物。
- 前記マイクロスフェアが、約0.5〜約20マイクロメートルの範囲の平均粒径を有する、請求項1に記載の組成物。
- 前記ガス気泡がフルオロカーボンガスを含む、請求項1に記載の組成物。
- 前記シェルがヒト血清アルブミンを含む、請求項1に記載の組成物。
- 前記活性型のABCA1が、配列番号1のアミノ酸配列を有する、請求項1に記載の組成物。
- 前記オープンリーディングフレームが、配列番号2のヌクレオチド配列を有する、請求項1に記載の組成物。
- 前記オープンリーディングフレームの発現を促進するように適合された前記少なくとも1つの配列が、サイトメガロウイルスプロモーターを含む、請求項1に記載の組成物。
- 前記プラスミドが、1ミリリットル当たり約0.5〜約50ミリグラムの範囲の濃度で組成物中に存在する、請求項1に記載の組成物。
- 前記マイクロスフェアが、1ミリリットル当たり約108〜約109マイクロスフェアの範囲の濃度で組成物中に存在する、請求項1に記載の組成物。
- 前記水性担体が、生理学的なpHに緩衝化されていてもよい生理食塩水を含む、請求項1に記載の組成物。
- (a)脂質代謝または輸送に関連する状態を治療するための薬物、(b)輸送の脂質代謝に関与するABCA1以外の酵素をコードするプラスミド、および(c)脂質代謝または輸送に関与する酵素を標的とするsiRNAをコードするプラスミド、からなる群から選択される少なくとも1つの物質をさらに含む、請求項1に記載の組成物。
- ABCA1をコードするプラスミドが、(a)輸送の脂質代謝に関与するABCA1以外のタンパク質および(b)脂質代謝または輸送に関与するタンパク質を標的とするsiRNAからなる群から選択される少なくとも1つの物質をまたコードする、請求項1に記載の組成物。
- 細胞をトランスフェクトするのに有用な組成物であって、前記組成物が、1ミリリットル当たり約0.5〜約50ミリグラムの、活性型のATP結合カセットトランスポーターA1(ABCA1)をコードするプラスミドベクターと、1ミリリットル当たり約108〜約109マイクロスフェアの、音響化学的に活性なマイクロスフェアとの混合物を、薬学的に許容される水性担体中に含み、前記ベクターが、前記活性型のABCA1をコードする発現可能なオープンリーディングフレームと、哺乳動物細胞内で前記オープンリーディングフレームの発現を促進するように適合された少なくとも1つの配列とを含み、前記音響化学的に活性なマイクロスフェアが、ヒト血清アルブミンを含むシェルに封入されたフルオロカーボンガス気泡を含み、前記マイクロスフェアは超音波音響エネルギーへの暴露によって崩壊可能であり、崩壊して前記封入されたガス気泡を放出するものである、前記組成物。
- 前記活性型のABCA1が、配列番号1のアミノ酸配列を有する、請求項13に記載の組成物。
- 前記オープンリーディングフレームが、配列番号2のヌクレオチド配列を有する、請求項13に記載の組成物。
- 組織をin vivoでトランスフェクトして前記組織の細胞内で活性型のABCA1を発現させる方法であって、
(a)活性型のATP結合カセットトランスポーターA1(ABCA1)をコードするプラスミドベクターと、音響化学的に活性なマイクロスフェアとを、被験者に静脈内共投与する工程であって、前記ベクターが、前記活性型のABCA1をコードする発現可能なオープンリーディングフレームと、哺乳動物細胞内で前記オープンリーディングフレームの発現を促進するように適合された少なくとも1つの配列とを含み、前記音響化学的に活性なマイクロスフェアが、タンパク質、脂質またはそれらの組み合わせを含むシェルに封入されたガス気泡を含み、前記マイクロスフェアは超音波音響エネルギーへの暴露によって崩壊可能であり、崩壊して前記封入されたガス気泡を放出するものである、前記工程、
(b)組成物のプラスミドおよびマイクロスフェアが組織の脈管構造を循環する間に、トランスフェクトされた被験者の組織を超音波イメージングし、それによって組織の脈管構造中のマイクロスフェアの存在を検出する工程、ならびに
(c)マイクロスフェアが組織内に存在する間に、イメージングに必要とされるレベルよりも高い音響エネルギーレベルであって、かつマイクロスフェアを破壊しマイクロスフェアからガス気泡を放出させるのに十分なエネルギーレベルで、組織へ超音波エネルギーのパルスを照射する工程であって、超音波エネルギーのパルスおよびそれによるガス気泡の放出は、組織内の細胞の有孔性を一時的に増加させ、細胞内へのプラスミドの侵入を容易にさせるものである、前記工程
を含む前記方法。 - 前記マイクロスフェアが、約0.5〜約20マイクロメートルの範囲の平均粒径を有する、請求項16に記載の方法。
- 前記ガス気泡がフルオロカーボンガスを含む、請求項16に記載の方法。
- 前記シェルがヒト血清アルブミンを含む、請求項16に記載の方法。
- 前記活性型のABCA1が、配列番号1のアミノ酸配列を有する、請求項16に記載の方法。
- 前記オープンリーディングフレームの発現を促進するように適合された前記少なくとも1つの配列が、サイトメガロウイルスプロモーターを含む、請求項16に記載の方法。
- 前記プラスミドが、水性担体中で、1ミリリットル当たり約0.5〜約50ミリグラムの範囲の濃度で投与される、請求項16に記載の方法。
- 前記マイクロスフェアが、水性担体中で、1ミリリットル当たり約108〜約109マイクロスフェアの範囲の濃度で投与される、請求項16に記載の方法。
- 前記プラスミドおよび前記マイクロスフェアが、1つの水性担体中の混合物として投与される、請求項16に記載の方法。
- 前記プラスミドおよび前記マイクロスフェアが、別々の水性担体中で投与される、請求項16に記載の方法。
- 前記プラスミドおよび前記マイクロスフェアとともに、追加の生物学的活性剤が共投与される、請求項16に記載の方法。
- 前記追加の生物学的活性剤が、(a)脂質代謝または輸送に関連する状態を治療するための薬物、(b)輸送の脂質代謝に関与するABCA1以外のタンパク質をコードするプラスミド、および(c)脂質代謝または輸送に関与するタンパク質を標的とするsiRNAをコードするプラスミド、からなる群から選択される少なくとも1つの物質を含む、請求項26に記載の方法。
- 前記組織が、肝臓組織、腸実質組織またはそれらの組み合わせを含む、請求項16に記載の方法。
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