JP2022541030A - hnRNPA2B1の抗感染作用及びその応用 - Google Patents
hnRNPA2B1の抗感染作用及びその応用 Download PDFInfo
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Abstract
Description
(a)SEQ ID NO:2又はSEQ ID NO:4に示されたアミノ酸配列を有するポリペプチド;又は
(b)SEQ ID NO:2又はSEQ ID NO:4に示されたアミノ酸配列と相同であるか、又は配列同一性を有し(例えば80%以上の相同性、又は80%以上の配列同一性を有し、例えば80%、85%、90%、95%、98%、99%であり)、かつ感染を抑制する活性を有するタンパク質又はポリペプチド;又は
(c)(a)又は(b)のアミノ酸配列に、一つ又は複数のアミノ酸が置換、欠失又は付加されており、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有する、(a)又は(b)から誘導されるタンパク質又はポリペプチド。
(i)SEQ ID NO:1、SEQ ID NO: 3に示されたヌクレオチド配列を有する核酸分子;又は
(ii) ストリンジェントな条件下で、(i)に限定されるヌクレオチド配列とハイブリダイズする分子;
(iii)SEQ ID NO:1又はSEQ ID NO:3に示されたヌクレオチド配列と相同であるか、又は配列同一性を有し(例えば80%以上の相同性、又は80%以上の配列同一性を有し、例えば80%、85%、90%、95%、98%、99%であり)、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有するタンパク質又はポリペプチドをコードする核酸分子;
(iv)(i)又は(ii)又は(iii)のヌクレオチド配列から、一つ又は複数のヌクレオチドが置換、欠失又は付加されており、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有するタンパク質又はポリペプチドをコードする核酸分子。
一部の実施形態において、阻害剤は、hnRNPA2B1又は当該タンパク質をコードする核酸分子に対する抗体、siRNA (例えば、配列は、SEQ ID NO:5-8のいずれか一つに示されたsiRNA)、miRNA、アンチセンスオリゴヌクレオチド、アンタゴニスト、ブロッカーから選べられる。
(A)治療又は予防有効量の本開示のhnRNPA2B1、当該タンパク質をコードする核酸分子、その促進剤及び/又はその阻害剤;
(B)薬学的または免疫学的に許容できるキャリア又は賦形剤;
(C)任意的に、感染性疾患及び関連する疾患及び/又は症状を予防又は治療する一つ又は複数の他の活性物質。
(A)感染された細胞、組織または動物を候補物質によって処理すること;
(B)上記の細胞、組織または動物中のhnRNPA2B1または当該タンパク質をコードする核酸分子のレベルを検出すること;及び
(C)hnRNPA2B1又は当該タンパク質をコードする核酸分子のレベルは、候補物質に処理された前のレベル、又は正常な対照中のレベルより高いと、上記の候補物質は、hnRNPA2B1を促進することで感染を抵抗する作用を有することを判明すること。
本明細書で使用される場合、用語「hnRNPA2B1タンパク質(ポリペプチド)」、「hnRNPA2B1」は、互換可能に使用され、異種核リボ核タンパク質A2B1を指す。本開示のhnRNPA2B1タンパク質は、SEQ ID NO:1の配列(ヒトcDNA全長配列)又はSEQ ID NO: 3(マウスCDS配列)がコードするタンパク質、又はこれらのタンパク質のインターフェロンの発現を促進する作用を有する相同配列(例えば、本分野に既知されたデータベース又はアライメントソフトウェアで得られるhnRNPA2B1の相同配列)、変異体又は修飾形式であっても良い。例えば、上記のhnRNPA2B1タンパク質は、(a)SEQ ID NO:2又はSEQ ID NO: 4に示されたアミノ酸配列;又は(b)(a)のアミノ酸配列に、一つ又は複数のアミノ酸が置換、欠失又は付加されており、かつインターフェロンの発現を促進する活性を有する、(a)から誘導されるタンパク質又はポリペプチド;から選べられる。
本明細書で使用される場合、用語「hnRNPA2B1遺伝子」、「hnRNPA2B1コード遺伝子」、「hnRNPA2B1タンパク質コード遺伝子」又は「hnRNPA2B1をコードする核酸分子」は、互換可能に使用され、いずれも本開示に記載されたhnRNPA2B1タンパク質又はポリペプチドをコードするヌクレオチド配列を指し、例えばSEQ ID NO:1 (ヒトCDS)配列、SEQ ID NO: 3 (マウスCDS)配列に示されたヌクレオチド配列、ストリンジェントな条件下でこれらの配列とハイブリダイズする分子、又は上記の分子と高度的に相同するファミリー遺伝子分子であり、上記の遺伝子の発現は、インターフェロンの産生と影響に一定の促進効果をもたらす。hnRNPA2B1遺伝子は、ヒトとマウスで高度に保存される。ヒトのGene IDは3181で、マウスのGene IDは53379である。
本開示には、さらにhnRNPA2B1又はhnRNPA2B1のコード配列の「促進剤」に関する。用語「促進剤」又は「hnRNPA2B1又はそのコード配列の促進剤」は、互換可能に使用され、hnRNPA2B1又はそれをコードする核酸分子のレベル又は活性を向上できる物質を指す。本開示に用いられる促進剤は、hnRNPA2B1発現ベクター、外来hnRNPA2B1、hnRNPA2B1又はそのコード配列の裸のDNA、hnRNPA2B1又はそれをコードする配列のリポソームに封入されたDNA、hnRNPA2B1タンパク質を含むが、これらに限定されない。
本開示は、さらにhnRNPA2B1遺伝子を含むベクター、及び当該ベクターにより遺伝子工程で産生された宿主細胞、及びトランスジェニックで得られたhnRNPA2B1高発現トランスジェニック動物を含む。
(1)本開示のhnRNPA2B1タンパク質をコードするポリヌクレオチド(又は変異体)で、又は当該ポリヌクレオチドを含有する組え発現ベクターで、適当な宿主細胞を形質転換または形質導入する;
(2)適当な培地で宿主細胞を培養する;
(3)培地又は細胞からタンパク質又はポリペプチドを単離、精製する。
本開示は、例えば医薬品、医薬品組成物又はキット/キットである製品、を提供し、ただし、有効量の本開示のhnRNPA2B1又はhnRNPA2B1をコードする核酸分子、その促進剤又はその阻害剤、及び薬学的または免疫学的に許容できるキャリアを含む。本明細書で使用される場合、「活性物質」又は「本開示の活性物質」という用語は、互換可能に使用され、hnRNPA2B1又はhnRNPA2B1コード配列、その促進剤又はその阻害剤を指す。
以下、具体的な実施例を参照して、本開示をさらに説明する。これらの実施例は、本開示の範囲を限定するものではなく、本開示の単なる例示であることが理解されるべく。当業者は、本開示に対して適切な修正および変形を行うことができ、これらの修正および変形はすべて、本開示の範囲内である。
マウスの初代腹膜マクロファージの取得:C57BL/6マウス(6-8週齢、メス、上海必凱実験動物株式会社から購入)を採用し、3%チオグリコレート(Sigma-Aldrich会社から購入)溶液2mlを1回腹腔内注射し、3日後、マウスを頸椎脱臼により殺し、腹腔を無血清培地で洗浄し、吸引後の遠心分離により細胞を得た。
初代腹腔マクロファージを、DMEM培地で培養し、ヒトTHP1細胞(ATCCから購入)を、1640培地で培養した。細胞に、hnRNPA2B1に対する低分子干渉RNA(hnRNPA2B1 siRNA)およびモックコントロール(対照siRNA)をトランスフェクトした(トランスフェクション試薬INTERFERinは、Polyplus会社から購入した)。
hnRNPA2B1 siRNA配列:
マウスhnRNPAB1 siRNA:
5′-GAGGAAAUUAUGGAAGUGGTT-3′(センス、SEQ ID NO:5);
5′-CCACUUCCAUAAUUUCCUCCT-3′(アンチセンス、SEQ ID NO:6)。
5′-CUUUGGUGGUAGCAGGAACTT-3′(センス、SEQ ID NO:7);
5′-GUUCCUGCUACCACCAAAGTT-3′(アンチセンス、SEQ ID NO:8)。
5′-UUCUCCGAACGUGUCACGUTT-3′(センス、SEQ ID NO:9);
5′-ACGUGACACGUUCGGAGAATT-3′(アンチセンス、SEQ ID NO:10)。
まず、従来の方法に従って、hnRNPA2B1のcDNA(NM_182650)を、真核生物の発現ベクターpcDNA3.1プラスミド(Addgeneから購入)に導入し、hnRNPA2B1発現ベクターを構築した。
IFN-βの分泌状況を図5に示した。
hnRNPA2B1骨髄性細胞の条件付きノックアウトマウス(上海南方モデル生物テクノロジー株式会社から購入し、工法は、Jnyner AL. Gene Targeting, Oxford University Press.1994を参照)を構築し、CREエンドヌクレアーゼによって特異的に認識できるloxP配列を、Hnrnpa2b1遺伝子のエクソン2~6に付加した。Hnrnpa2b1fl/flマウスを、C57BL/6バックグラウンドに戻し交配し、次にLyz2-Creマウスと交雑し、骨髄性細胞にHnrnpa2b1遺伝子のエクソン2~6の特異的なノックアウトを達成した。Hnrnpa2b1fl/flLyz2-Cre+/-マウスとHnrnpa2b1fl/flLyz2-Cre-/-マウスの交配により、骨髄性細胞特異的なhnRNPA2B1ノックアウト(Hnrnpa2b1 cKO)マウスと同腹仔対照野生型マウスが得られ、これらのマウスは、特殊病原体フリー(SPF)環境で飼育された。
hnRNPA2B1骨髄性細胞の条件付きノックアウトマウスを構築した(実施例4と同じ)。野生型マウスと骨髄性細胞特異的なhnRNPA2B1ノックアウト(Hnrnpa2b1 cKO)マウスを、7×108プラーク形成単位(PFU)のHSV-1に腹腔内感染させ、4日後に、プラークアッセイで脳ウイルス力価を検出した。
結果は、hnRNPA2B1のノックアウトが、インビボでHSV-1ウイルスの複製を促進することを示し、hnRNPA2B1が抗感染に重要な役割を果たす可能性があることを示唆した。
hnRNPA2B1骨髄性細胞の条件付きノックアウトマウスを構築した(実施例3と同じ)。野生型マウスと骨髄性細胞特異的hnRNPA2B1ノックアウト(Hnrnpa2b1 cKO)マウスを、7×108プラーク形成単位(PFU)のHSV-1で腹腔内感染し、マウスの死亡を継続的に観察した。結果は、図8に示された。
hnRNPA2B1遺伝子エクソン2を、CRISPR/Cas9テクノロジーによって削除し、hnRNPA2B1をノックアウトしたRAW264.7細胞株を構築した。対照のRAW264.7細胞(ATCCから購入)と、hnRNPA2B1をノックアウトしたRAW264.7細胞とを、AdV(MOI、10;Ad5タイプ、漢恒バイオテクノロジー(上海)株式会社から購入)に感染させ、感染の7時間後に、付着細胞を回収し、細胞の総RNAを抽出し、リアルタイム蛍光定量PCRでIFN-βのmRNAの発現レベルを検出した。
Claims (10)
- 感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する製品の調製における異種核リボ核タンパク質A2B1(hnRNPA2B1)、当該タンパク質をコードする核酸分子、その促進剤又はその阻害剤の用途。
- 上記のhnRNPA2B1は、以下から選べられる:
(a)SEQ ID NO:2又はSEQ ID NO:4に示されたアミノ酸配列を有するポリペプチド;又は
(b)SEQ ID NO:2又はSEQ ID NO:4に示されたアミノ酸配列と相同であるか、又は配列同一性を有し(例えば80%以上の相同性、又は80%以上の配列同一性を有し、例えば80%、85%、90%、95%、98%、99%であり)、かつ感染を抑制する活性を有するタンパク質又はポリペプチド;又は
(c)(a)又は(b)のアミノ酸配列に、一つ又は複数のアミノ酸が置換、欠失又は付加されており、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有する、(a)又は(b)から誘導されるタンパク質又はポリペプチド;及び/又は
上記の核酸分子は、以下から選べられる:
(i)SEQ ID NO:1、SEQ ID NO: 3に示されたヌクレオチド配列を有する核酸分子;又は
(ii)ストリンジェントな条件下で、(i)に限定されるヌクレオチド配列とハイブリダイズする分子;
(iii)SEQ ID NO:1又はSEQ ID NO:3に示されたヌクレオチド配列と相同であるか、又は配列同一性を有し(例えば80%以上の相同性、又は80%以上の配列同一性を有し、例えば80%、85%、90%、95%、98%、99%であり)、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有するタンパク質又はポリペプチドをコードする核酸分子;
(iv)(i)又は(ii)又は(iii)のヌクレオチド配列から、一つ又は複数のヌクレオチドが置換、欠失又は付加されており、かつ感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療する活性を有するタンパク質又はポリペプチドをコードする核酸分子;及び/又は
上記の促進剤は、hnRNPA2B1タンパク質レベルを向上又はhnRNPA2B1機能を促進する物質であり、例えばhnRNPA2B1又はhnRNPA2B1をコードする配列の過剰発現ベクター;外来hnRNPA2B1;hnRNPA2B1をコードする配列の裸のDNA;hnRNPA2B1をコードする配列のリポソームに封入されたDNA;インビボでhnRNPA2B1に変換することができるhnRNPA2B1前駆体タンパク質又はコンジュゲート又はコンプレックスから選べられる;及び/又は
上記の阻害剤は、hnRNPA2B1又は当該タンパク質をコードする核酸分子に対する抗体、siRNA、miRNA、アンチセンスオリゴヌクレオチド、アンタゴニスト、ブロッカーから選べられる;ことを特徴とする請求項1に記載された用途。 - 上記の感染は、DNAが関与及び/又は仲介する感染であることを特徴とする請求項1に記載された用途。
- 上記の感染は、DNAが関与及び/又は仲介するウイルス感染、バクテリア感染、真菌感染又はその組み合わせであることを特徴とする請求項1に記載された用途。
- 上記の感染は、単純ヘルペスウイルス、B型肝炎ウイルス、アデノビルス、ポックスウイルス、小DNAウイルス、アデノ随伴ウイルスの一種類又は複数種類のウイルスに引かれる感染から選べられるDNAウイルス感染であることを特徴とする請求項1に記載された用途。
- 上記の感染に関与する疾患及び/又は症状は、感染による病理学的損傷;感染後のサイトカイン(例えばインターフェロン)の不十分または過剰な産生;内毒素性ショックまたは死;臓器への炎症性損傷;多臓器不全、例えば、上記の臓器は、肝臓、脾臓、脳、腎臓、心臓、肺、胃、腸から選べられる;ウイルス感染による慢性炎症性疾患(例えば、炎症性腸疾患、関節リウマチ、全身性エリテマトーデス、慢性腎炎、結核、慢性胃腸疾患などの自己免疫疾患)から選べられる一つ又は複数であることを特徴とする請求項1に記載された用途。
- 上記の製品は、医薬品組成物又はキットであり、例えば、その形式は、経口、注射(例えば裸のDNAまたはタンパク質の直接注入、リポソームに封入されたDNA又はタンパク質の注入)、金でコーティングされた遺伝子銃の爆撃、生殖欠損菌を含むプラスミドDNAの持ち、標的DNAを運ぶ複製欠損アデノウイルス、又は目的遺伝子がコードするタンパク質、エレクトロポレーション、経鼻投与、肺投与、経口投与、経皮投与、腫瘍内投与から選べられる医薬品組成物又はキットによる投与に適した形式形態であることを特徴とする請求項1に記載された用途。
- 上記の製品は、さらに、感染性疾患及び/又は感染に関与する疾患及び/又は症状を予防及び/又は治療するための他の物質を含み、他の活性物質は、例えば、β-ラクタム系抗生物質(ペニシリンとセファロスポリン)、アミノグリコシド系抗生物質、テトラサイクリン系抗生物質、クロラムフェニコール系抗生物質、マクロライド系抗生物質、抗真菌性抗生物質、抗結核系抗生物質など、一般的に使用される臨床用抗生物質;一般的に使用される臨床抗ウイルス薬(三環式アミン、ピロリン酸塩、プロテアーゼ阻害剤、ヌクレオシド薬とインターフェロン、アンチセンスオリゴヌクレオチドなど);一般的に使用される臨床免疫抑制剤(グルココルチコイド、シクロホスファミド、クロロキン、シクロスポリンA、トリプテリギウムウィルフォルディ、漢方薬、抗TNFモノクローナル抗体を含む)から選べられる一つ又は複数を含むことを特徴とする請求項1に記載された用途。
- (A)治療又は予防有効量のhnRNPA2B1、当該タンパク質をコードする核酸分子及び/又はその促進剤;
(B)薬学的または免疫学的に許容できるキャリア又は賦形剤;
(C)任意的に、感染性疾患及び関連する疾患及び/又は症状を予防又は治療する一つ又は複数の他の活性物質;を含む医薬品組成物又はキット。 - (A)感染された細胞、組織または動物を候補物質によって処理すること;
(B)上記の細胞、組織または動物中のhnRNPA2B1または当該タンパク質をコードする核酸分子のレベルを検出すること;及び
(C)hnRNPA2B1又は当該タンパク質をコードする核酸分子のレベルは、候補物質に処理された前のレベル、又は正常な対照中のレベルより高いと、上記の候補物質は、hnRNPA2B1を促進することで感染を抵抗する作用を有することを判明すること;を含むhnRNPA2B1を促進することで感染を抵抗する医薬品をスクリーニングする方法。
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