JP5530933B2 - 第vii因子遺伝子発現阻害のための組成物及び方法 - Google Patents
第vii因子遺伝子発現阻害のための組成物及び方法 Download PDFInfo
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- JP5530933B2 JP5530933B2 JP2010538109A JP2010538109A JP5530933B2 JP 5530933 B2 JP5530933 B2 JP 5530933B2 JP 2010538109 A JP2010538109 A JP 2010538109A JP 2010538109 A JP2010538109 A JP 2010538109A JP 5530933 B2 JP5530933 B2 JP 5530933B2
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Description
本出願は、2007年12月10日に出願された米国仮出願第61/012,670号、及び2007年12月19日に出願された米国仮出願第61/014,879号の利益を主張する。これら両方の先行出願がその全体を参照することにより本明細書に組み込まれる。
(a)二本鎖リボ核酸(dsRNA)であって、互いに相補的、例えば、実質的に又は完全に、互いに相補的な少なくとも2つの配列が含まれるdsRNAの細胞内導入工程、及び
(b)工程(a)において産生した細胞を第VII因子遺伝子のmRNA転写物を分解させるのに十分な時間維持し、それによって細胞内第VII因子遺伝子の発現を阻害する工程。
(項目1)
二本鎖リボ核酸(dsRNA)であって、上記dsRNAが実質的に互いに相補的な少なくとも2つの配列を含み、dsRNAのセンス鎖が第一配列を含み、dsRNAのアンチセンス鎖が第VII因子をコードするmRNAの少なくとも一部に実質的に相補的な領域を含む第二配列を含み、上記領域が長さ30ヌクレオチド未満であり、上記第一配列が表1、2、及び3の上記センス鎖配列からなる群から選択され、上記第二配列が表1、2、及び3の上記アンチセンス鎖配列からなる群から選択されるdsRNA。
(項目2)
センス鎖配列が配列番号5の配列を含み、アンチセンス鎖配列が配列番号6の配列を含む、項目1に記載のdsRNA。
(項目3)
98Nl2‐5で製剤化した第VII因子標的siRNAの単回投与によって少なくとも25%発現抑制することにより、dsRNAがラット肝第VII因子mRNAレベルを低減し得る、項目1に記載のdsRNA。
(項目4)
上記dsRNAが少なくとも1つの修飾ヌクレオチドを含む、項目1に記載のdsRNA。
(項目5)
上記修飾ヌクレオチドが、2’‐O‐メチル修飾ヌクレオチド、5’‐ホスホロチオエート基含有ヌクレオチド、及びコレステリル誘導体又はドデカン酸ビスデシルアミド基に連結した末端ヌクレオチドからなる群から選択される、項目4に記載のdsRNA。
(項目6)
上記修飾ヌクレオチドが、2’‐デオキシ‐2’‐フルオロ修飾ヌクレオチド、2’‐デオキシ修飾ヌクレオチド、ロックトヌクレオチド、脱塩基性ヌクレオチド、2’‐アミノ修飾ヌクレオチド、2’‐アルキル修飾ヌクレオチド、モルホリノヌクレオチド、ホスホラミデート、及びヌクレオチド含有非天然塩基からなる群から選択される、項目4に記載のdsRNA。
(項目7)
ホスホロチオエート又は2’修飾ヌクレオチドを含む、項目1に記載のdsRNA。
(項目8)
相補性領域が少なくとも15ヌクレオチドの長さである、項目1に記載のdsRNA。
(項目9)
相補性領域が19〜21ヌクレオチドの長さである、項目1に記載のdsRNA。
(項目10)
項目1に記載のdsRNAを含む細胞。
(項目11)
項目1に記載のdsRNA及び製薬上許容可能な担体を含む医薬組成物。
(項目12)
細胞内VII因子遺伝子発現の阻害方法であって、
(a)項目1に記載の二本鎖リボ核酸(dsRNA)を細胞内に導入する工程と、
(b)工程(a)において産生される細胞を、第VII因子遺伝子のmRNA転写産物を分解するのに十分な時間維持し、それによって細胞内の第VII因子遺伝子発現を阻害する工程とを含む方法。
(項目13)
ウイルス性出血性発熱の治療、予防又は管理を必要とする患者に対する項目1に記載のdsRNAの治療的又は予防的有効量の投与を含む、ウイルス性出血性発熱の治療、予防又は管理方法。
(項目14)
項目1に記載のdsRNAの少なくとも一方の鎖をコードするヌクレオチド配列に作動可能に連結した調節配列を含むベクター。
(項目15)
項目14に記載のベクターを含む細胞。
本発明の1つ以上の実施形態の詳細を本明細書で下に説明する。本発明の他の特徴、目的、及び利点は本明細書及び図面から、並びに請求項から明らかとなるであろう。
便宜上、本明細書、実施例、及び添付の請求項で使用されるある用語及び語句の意味を下に提供する。本明細書の他の箇所における用語の使用法と本項で提供するその定義との間に明らかな矛盾があった場合、本項の定義が優先されるものとする。
[(対照細胞内のmRNA)−(処理した細胞内のmRNA)]/(対照細胞内のmRNA)×100%
と表される。
一実施形態では、本発明は細胞内又は哺乳類内において第VII因子遺伝子発現を阻害する二本鎖リボ核酸(dsRNA)分子を提供する。該dsRNAには、第VII因子遺伝子発現で形成されたmRNAの対応領域に相補的であり、長さ30ヌクレオチド未満であり、通常、長さ19〜24ヌクレオチドである相補性領域を含むアンチセンス鎖が含まれる。一実施形態ではdsRNAは、前記VII因子遺伝子発現細胞との接触時、前記VII因子遺伝子発現を、例えば、細胞ベースの検定において、少なくとも25%、例えば、少なくとも40%阻害する。dsRNAには二重鎖構造を形成するハイブリダイズに十分相補的な2本のRNA鎖が含まれる。センス鎖には、適切な条件下で結合した場合、二本鎖がハイブリダイズして二重鎖構造を形成するように、アンチセンス鎖に相補的な領域が含まれる。一般的に、二重鎖構造は15〜30、より通常では18〜25、さらにより通常では19〜24、及び最も通常では21〜23塩基対の長さである。同様に、標的配列への相補性領域は15〜30、より通常では18〜25、さらにより通常では19〜24、及び最も通常では21〜23ヌクレオチドの長さである。FVIIを標的とするdsRNAはさらに1つ又は複数の単鎖ヌクレオチド突出部を含んでよい。dsRNAは当分野で知られている標準方法によって、以下で詳細に考察するように、例えばBiosearch、Applied Biosystems, Inc.から市販されている自動DNA合成装置の使用などによって合成し得る。一実施形態では、第VII因子遺伝子はヒト第VII因子遺伝子である。特定の実施形態では、第一配列は表1、2、及び3のセンス配列からなる群から選択され、第二配列は表1、2、及び3のアンチセンス配列からなる群から選択される。一実施形態では、切断は表1、2、及び3のdsRNAの切断部位の6、5、4、3、2又は1ヌクレオチド以内である。
上記のいくつかの修飾した核酸塩基並びに 他の修飾した核酸塩基の調製を説明している代表的な米国特許は、参照することにより各々が本明細書に組み込まれる米国特許第4,845,205号、第5,130,30号、第5,134,066号、第5,175,273号、第5,367,066号、第5,432,272号、第5,457,187号、第5,459,255号、第5,484,908号、第5,502,177号、第5,525,711号、第5,552,540号、第5,587,469号、第5,594,121号、第5,596,091号、第5,614,617号、及び第5,681,941号と同様に上記の米国特許第3,687,808号を含むが、これらに限定されず、米国特許第5,750,692号も含まれ、それも参照することにより本明細書に組み込まれる。
FVIIを標的とするdsRNAはin vivoで細胞内にて組換えウイルスベクターからも発現し得る。例えば、組換えウイルスベクターは、dsRNA及びdsRNA配列発現のための任意の適切なプロモーターをコードする配列を含み得る。適切なプロモーターとしては、例えば、U6又はHl RNA pol IIIプロモーター配列及びサイトメガロウイルスプロモーターが挙げられる。他の適切なプロモーターの選択は当分野における技術範囲である。組換えウイルスベクターは特定の組織内又は特定の細胞内環境におけるdsRNA発現を誘導可能な又は調節可能なプロモーターも含み得る。dsRNAをin vivo細胞内に送達するための組換えウイルスベクターの使用についての詳細は、以下で考察する。
一実施形態では、本発明は本明細書に記載のdsRNA、及び製薬上許容可能な担体を含む医薬組成物を提供する。dsRNAを含む医薬組成物は第VII因子発現が介在した病的プロセスなど、第VII因子遺伝子の発現又は活性に関連した疾患又は障害の治療に有用である。そのような医薬組成物は送達様式に基づき製剤化される。一例は非経口送達を介した全身投与用に製剤化した組成物である。
本発明の組成物は乳剤として調製及び製剤化されてよい。乳剤は典型的には一方の液体が他方の中に通常は直径0.1μmを超える小滴形態で分散している不均質な系である(Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p.199、 Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p.245、 Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p.335、 Higuchi et al, in Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p.301)。乳剤は、互いによく混合かつ分散された非混和性の2つの液相を含む二相系であることが多い。一般に、乳剤は、油中水(w/o)型又は水中油(o/w)型のどちらであってもよい。水相が大量の油相中で微細に分割され細かい小滴として分散される場合、生成組成物は油中水(w/o)型乳剤と呼ばれる。あるいは、油相が大量の水相中で微細に分割され細かい小滴として分散される場合、生成組成物は水中油(o/w)型乳剤と呼ばれる。乳剤は、分散相と、さらに水相、油相中又はそれ自体が分離した相の溶液として存在する可能性のある活性薬物とに加えて追加の構成成分を含んでよい。乳化剤、安定剤、染料及び酸化防止剤のような医薬賦形剤が、必要に応じて乳剤中に存在していてもよい。医薬乳剤は3つ以上の相で構成される多相乳剤、例えば油中水中油(o/w/o)型乳剤及び水中油中水(w/o/w)型乳剤の事例のようなものであってもよい。そのような複雑な製剤は、単純な二成分の乳剤にはないある種の利点を備えていることが多い。o/w型乳剤の個々の油の小滴がより小さな水滴を囲む多相乳剤は、w/o/w型乳剤を構成する。同様に、油性連続相中で安定化した水の小球に囲まれた油の小滴の系は、o/w/o型乳剤を提供する。
マイクロエマルジョンの他に、研究され、薬物の製剤化に使用されている、多くの組織化された界面活性剤構造物がある。これらには単層、ミセル、二層及び小胞が挙げられる。リポソームのような小胞は、その特異性及び作用持続時間ゆえに、薬物送達の見地から大きな関心が持たれている。本発明において使用されるとき、「リポソーム」という用語は、球状の1つ又は複数の二層をなすように配置された両親媒性脂質で構成されている小胞を意味する。
一実施形態では、本発明は、動物の皮膚への核酸、特にdsRNAの効率的な送達を達成するために様々な浸透促進剤を使用する。ほとんどの薬物は、イオン化及び非イオン化の両方の状態で溶液中に存在する。しかしながら、通常は脂溶性又は親油性の薬物だけが容易に細胞膜を横断する。横断しようとする細胞膜が浸透促進剤で処理されると、親油性ではない薬物ですら細胞膜を横断する可能性が見出されてきている。浸透促進剤は、親油性ではない薬物が細胞膜を横切って拡散するのを支援することに加えて、親油性の薬物の透過性も高める。
本発明のある種の組成物は、製剤中に担体化合物も組み入れる。本明細書において使用するとき、「担体化合物」又は「担体」とは、核酸又はそのアナログであって、不活性である(すなわち、それ自身は生物学的活性を有していない)が、例えば生物学的活性を有する核酸の分解又は循環血中からの除去促進により生物学的活性を有する核酸のバイオアベイラビリティを低減するin vivoプロセスにより核酸として認識されるものを指し得る。核酸及び担体化合物を、典型的には担体化合物を過剰量として併用投与すると、おそらくは共通の受容体に関する担体化合物と核酸との間の競合により、肝臓、腎臓又は他の循環血流外の蓄積部位で回収される核酸の量を大幅に低減し得る。例えば、部分的にホスホロチオエートを有するdsRNAをポリイノシン酸、硫酸デキストラン、ポリシチジル酸又は4‐アセトアミド‐4’イソチオシアノ‐スチルベン‐2,2’‐ジスルホン酸と共に併用投与すると、該dsRNAの肝臓組織での回収は低減し得る(Miyao et al, DsRNA Res. Dev., 1995, 5, 115−121、 Takakura et al., DsRNA & Nucl. Acid Drug Dev., 1996, 6, 177−183)。
担体化合物とは対照的に、「医薬担体」すなわち「賦形剤」は、製薬上許容可能な溶媒、懸濁化剤、又は動物に1つ又は複数の核酸を送達するための他の任意の薬理学的に不活性なビヒクルである。賦形剤は液体でも固体でもよく、想定された投与方法によって、所与の医薬組成物の核酸及び他の成分と組み合わせたときに所望の体積、粘稠度などを提供するように選択される。代表的な医薬担体には、限定するものではないが、結合剤(例えば、予めゼラチン化したトウモロコシ澱粉、ポリビニルピロリドン又はヒドロキシプロピルメチルセルロースなど)、増量剤(例えば、ラクトース及びその他の糖、微結晶性セルロース、ペクチン、ゼラチン、硫酸カルシウム、エチルセルロース、ポリアクリレート又はリン酸水素カルシウムなど)、滑剤(例えば、ステアリン酸マグネシウム、タルク、シリカ、コロイド状二酸化ケイ素、ステアリン酸、ステアリン酸の金属塩、水素化植物油、トウモロコシ澱粉、ポリエチレングリコール、安息香酸ナトリウム、酢酸ナトリウムなど)、崩壊剤(例えば、澱粉、澱粉グリコール酸ナトリウムなど)、並びに湿潤剤(例えば、ラウリル硫酸ナトリウムなど)が挙げられる。
本発明の組成物は、通常、医薬組成物中に見出される他の補助成分を、該成分の分野で確立された使用量レベルで、付加的に含んでよい。したがって、例えば、組成物は、追加の、混合可能な、薬学的活性物質、例えば止痒剤、収斂剤、局所麻酔薬又は抗炎症薬などを含んでもよく、又は本発明の組成物の様々な剤形を物理的に製剤化するのに役立つ追加の物質、例えば色素、香料剤、保存剤、酸化防止剤、乳白剤、増粘剤及び安定剤などを含んでもよい。しかしながら、そのような物質を加える場合は、該物質は本発明の組成物成分の生物学的活性を過度に妨げてはならない。製剤は滅菌し得て、望ましい場合は、該製剤の核酸との間で有害な相互反応を生じない補助的薬剤、例えば滑剤、保存剤、安定剤、湿潤剤、乳化剤、浸透圧を操作するための塩類、緩衝液、着色剤、香味料及び/又は芳香剤などと混合し得る。
一実施形態では、本発明は、ウイルス性出血性発熱などの第VII因子遺伝子発現介在性病状を有する対象の治療方法を提供する。本実施形態では、dsRNAは第VII因子発現蛋白質制御のための治療剤として作用する。該方法には第VII因子遺伝子発現が抑制されるように、ウイルス感染患者などの患者(例えば、ヒト)への医薬組成物投与が含まれる。それらの高い特異性により、本発明で特徴とされるdsRNAは特異的に第VII因子遺伝子のmRNAを標的とする。
さらに別の態様では、本発明は哺乳類内の第VII因子遺伝子発現の阻害方法を提供する。該方法は標的VII因子遺伝子発現が抑制されるような、本発明で特徴とされる組成物の哺乳類への投与を含む。それらの高い特異性のために、本発明で特徴とされるdsRNAは特異的に標的VII因子遺伝子のRNA(一次又はプロセシング後)を標的とする。dsRNAを使用した第VII因子遺伝子発現阻害の組成物及び方法は、本明細書の他の箇所に記載されているように実施し得る。
別の態様では、FVII遺伝子発現活性を調節するFVII特異的dsRNA分子はDNA又はRNAベクター内に挿入した転写単位によって発現する(例えば、Couture, A, et al., TIG. (1996), 12:5−10; Skillern, A., et al., 国際公開第00/22113号、Conrad、国際公開第00/22114号、及びConrad、米国特許第6,054,299号を参照のこと)。これらのトランス遺伝子は直鎖状コンストラクト、環状プラスミド、又はウイルスベクターとして挿入し得、これらは宿主ゲノム内へ統合されたトランス遺伝子として取り込まれ且つ遺伝し得る。トランス遺伝子はまた染色体外プラスミドとして遺伝されるのを可能にするよう構築され得る(Gassmann, et al., Proc. Natl. Acad. ScL USA (1995) 92:1292)。
FVII標的siRNAの設計。凝固第VII因子(AI132620、Cf7、凝固第VII因子前駆体、凝固第VII因子、FVII、血清プロトロンビン転化促進因子、FVII凝固蛋白質、及びエプタコグアルファとしても知られる)を標的とするsiRNAを同定するためにsiRNA設計を実施した。
in vivoのFVIIサイレンシング。ラット(n=4)に脂質様製剤98N12‐5で製剤化したsiFVIIを1.25、2.5、3、3.5、4、5、及び10mg/kg単回静脈注射した。
ウイルス性出血性発熱治療標的としての第VII因子。マウス肝細胞内VII因子の頑強なin vivo発現抑制が脂質で製剤化したFVIIdsRNA(LNP‐01 FVII)投与後に観察された(図4)。マウスにdsRNAを静脈内投与し、24時間後FVII蛋白質について血清を分析した。FVII蛋白質レベルの用量依存的な低下が生じた。LNP‐01で製剤化したルシフェラーゼsiRNAを陰性対照として使用した。
siFVIIによる治療は長期の効果を示した。
dsRNAの合成
試薬の供給源
試薬の供給源が本明細書中で特に記載されない場合、そのような試薬は、分子生物学において適用するための品質/純度標準の分子生物学用試薬を供給する任意の業者から入手することができる。
単鎖RNAをExpedite 8909シンセサイザー(Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany)、及び固体支持体として制御細孔ガラス(CPG, 500Å, Proligo Biochemie GmbH, Hamburg, Germany)使用して、固体相合成によって1μM規模で産生した。RNA及び2’‐O‐メチルヌクレオチド含有RNAを各々対応するホスホラミダイト及び2’‐O‐メチルホスホラミダイト(Proligo Biochemie GmbH, Hamburg, Germany)を使用して、固体相合成によって作製した。これら構成要素は、Current protocols in nucleic acid chemistry、Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USAに記載されているような標準ヌクレオシドホスホラミダイトを使用してオリゴリボヌクレオチド鎖の配列内の選択部位に組み込んだ。ホスホロチオエート連結はヨウ素酸化剤溶液をBeaucage試薬(Chruachem Ltd, Glasgow, UK)のアセトニトリル溶液(1%)と置換して導入した。さらに補助試薬をMallinckrodt Baker (Griesheim, Germany)から得た。
Claims (21)
- 二本鎖リボ核酸(dsRNA)であって、該dsRNAは、30ヌクレオチド未満であり、かつ実質的に互いに相補的な少なくとも2つの配列を含み、該dsRNAのセンス鎖が第一配列を含み、該dsRNAのアンチセンス鎖が第VII因子をコードするmRNAに相補的な領域を含む第二配列を含み、該相補的な領域が長さ30ヌクレオチド未満であり、該第二配列が配列番号2のヌクレオチド配列の少なくとも15の隣接ヌクレオチドを含む、dsRNA。
- 98Nl2‐5で製剤化した第VII因子標的siRNAの単回投与によって少なくとも25%発現抑制することにより、前記dsRNAがラット肝第VII因子mRNAレベルを低減する、請求項1に記載のdsRNA。
- 前記センス鎖またはアンチセンス鎖の少なくとも1つのヌクレオチドは、修飾ヌクレオチドである、請求項1に記載のdsRNA。
- 前記修飾ヌクレオチドが、2’‐O‐メチル修飾ヌクレオチド、5’‐ホスホロチオエート基含有ヌクレオチド、及びコレステリル誘導体又はドデカン酸ビスデシルアミド基に連結した末端ヌクレオチドからなる群から選択される、請求項3に記載のdsRNA。
- 前記修飾ヌクレオチドが、2’‐デオキシ‐2’‐フルオロ修飾ヌクレオチド、2’‐デオキシ修飾ヌクレオチド、ロックトヌクレオチド、脱塩基性ヌクレオチド、2’‐アミノ修飾ヌクレオチド、2’‐アルキル修飾ヌクレオチド、モルホリノヌクレオチド、ホスホラミデート、及びヌクレオチド含有非天然塩基からなる群から選択される、請求項3に記載のdsRNA。
- 前記修飾ヌクレオチドが、ホスホロチオエート又は2’修飾ヌクレオチドを含む、請求項3に記載のdsRNA。
- 前記相補的な領域が少なくとも15ヌクレオチドの長さである、請求項1に記載のdsRNA。
- 前記相補的な領域が19〜21ヌクレオチドの長さである、請求項1に記載のdsRNA。
- 前記第二配列が、配列番号2のヌクレオチド配列を含む、請求項1に記載のdsRNA。
- 前記第一配列が、配列番号1のヌクレオチド配列を含む、請求項1に記載のdsRNA。
- 前記第二配列が、配列番号2のヌクレオチド配列からなる、請求項1に記載のdsRNA。
- 前記第一配列が、配列番号1のヌクレオチド配列からなる、請求項1に記載のdsRNA。
- 前記第二配列は、配列番号2のヌクレオチド配列を含み、前記第一配列は、配列番号1のヌクレオチド配列を含む、請求項1に記載のdsRNA。
- 前記第二配列は、配列番号2のヌクレオチド配列からなり、前記第一配列は、配列番号1のヌクレオチド配列からなる、請求項1に記載のdsRNA。
- 請求項1に記載のdsRNAの少なくとも1つの鎖をコードするヌクレオチドに作動可能に連結された調節配列を含む、ベクター。
- 請求項15に記載のベクターを含む細胞。
- 請求項1に記載のdsRNAを含む細胞。
- 請求項1に記載のdsRNA及び製薬上許容可能な担体を含む医薬組成物。
- 細胞内VII因子遺伝子発現の阻害のための、請求項1に記載のdsRNAを含む組成物であって、該dsRNAが該細胞内に導入され、該細胞が、第VII因子遺伝子のmRNA転写産物を分解するのに十分な時間維持される、組成物。
- ウイルス性出血性発熱の治療又は管理のための、請求項1に記載のdsRNAの治療的有効量を含む、組成物。
- 細胞内VII因子遺伝子発現の阻害のためのインビトロの方法であって、
(a)請求項1に記載のdsRNAを細胞内に導入する工程と、
(b)工程(a)において産生される細胞を、第VII因子遺伝子のmRNA転写産物を分解するのに十分な時間維持し、それによって細胞内の第VII因子遺伝子発現を阻害する工程とを含む方法。
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AU2008335202A1 (en) | 2009-06-18 |
US20090264511A1 (en) | 2009-10-22 |
WO2009076400A3 (en) | 2009-07-30 |
US20120208860A1 (en) | 2012-08-16 |
EP2245159A2 (en) | 2010-11-03 |
US7871985B2 (en) | 2011-01-18 |
EP2617828B1 (en) | 2014-09-24 |
EP2617828A1 (en) | 2013-07-24 |
US20140343122A1 (en) | 2014-11-20 |
US8334273B2 (en) | 2012-12-18 |
JP2011505833A (ja) | 2011-03-03 |
US20160017336A1 (en) | 2016-01-21 |
EP2848688A1 (en) | 2015-03-18 |
US20130184326A1 (en) | 2013-07-18 |
WO2009076400A2 (en) | 2009-06-18 |
US8664193B2 (en) | 2014-03-04 |
CA2707042A1 (en) | 2009-06-18 |
US9062310B2 (en) | 2015-06-23 |
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