JP6265940B2 - ポリグルタミンタンパク質発現の選択的阻害 - Google Patents
ポリグルタミンタンパク質発現の選択的阻害 Download PDFInfo
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Description
連邦政府によって支援される研究または開発に関する陳述
本発明は、National Institutes of Health-NIGMSによって与えられた助成金番号60642の下での政府支援によって一部なされた。米国政府は、本発明においてある一定の権利を有する。
本出願は、2008年7月29日に出願された米国仮出願第61/084,350号に対する優先権の恩典を主張し、この全内容は、参照により本明細書に組み入れられる。
A.発明の分野
本発明は、生物学および医学の分野に関する。より特には、本発明は、ハンチンチンおよびアタキシン1〜3などの、トリプレットコードされる疾患タンパク質発現の選択的阻害のための組成物および方法を提供する。
ハンチントン病(HD)は、欧州および北米において100,000人当たり5〜10人の罹患率を有する常染色体優性遺伝性疾患である(Borrell-Pages et al., 2004;Walker, 2007)。HDは、タンパク質機能の崩壊および神経変性をもたらす、ハンチンチン(HTT)遺伝子の第1エキソン内のCAGトリヌクレオチドリピートの伸長によって引き起こされる(Gusella and MacDonald, 2006)。HTT発現を減少させるアンチセンスオリゴヌクレオチドまたはsiRNAが、治療戦略として提案され(Hasholt et al., 2003;Boado et al., 2002;Harper et al., 2005;Denovan-Wright and Davidson, 2006;DiFiglia et al., 2007)、しかし、大抵のオリゴマーは、突然変異および野生型タンパク質発現を無差別に阻害する。HTTは、胚形成(Nasir et al., 1995)、神経発生(White et al., 1997)、およびヘテロ接合体における正常な成体機能(Nasir et al., 1995)において必須の役割を果たすことが公知であり、このことは、突然変異HTTおよび野生型HTTの両方を阻害する薬剤は、顕著な副作用を誘発することを示唆している。HDおよび他の神経疾患について突然変異対立遺伝子と野生型対立遺伝子とを識別するための1つの戦略は、単一ヌクレオチド差異を標的化するsiRNAを使用する(Schwarz et al., 2006;Rodriguez-Lebron and Paulson, 2006)。これらの多型性は、しばしば患者ごとに相違し、病院における対立遺伝子特異的RNAiの適用を複雑にする。従って、突然変異HTT産生を選択的に阻害する薬剤を同定する必要性が存在するままである。
[本発明1001]
伸長したトリヌクレオチドリピート領域を有するmRNAによってコードされる疾患タンパク質の発現を阻害するための方法であって、該疾患タンパク質を産生する細胞と、該mRNAの該リピート領域を標的化する一定量の核酸アナログとを接触させる工程を含み、ここで、(i)阻害が、mRNAが伸長したトリヌクレオチドリピート領域を欠いている該疾患タンパク質の正常形態よりも該疾患タンパク質について選択的であり、かつ(ii)阻害が、該mRNAの産生に実質的に影響を与えない、前記方法。
[本発明1002]
前記リピート領域が、約125リピート以下のサイズである、本発明1001の方法。
[本発明1003]
前記疾患タンパク質が、ハンチンチン、アタキシン-3、アタキシン-1、アタキシン-2またはアトロフィン1である、本発明1002の方法。
[本発明1004]
前記核酸アナログが、約7〜約30塩基長である、本発明1001の方法。
[本発明1005]
前記核酸アナログが、ペプチド核酸(PNA)である、本発明1001の方法。
[本発明1006]
前記PNAが、カチオン性ペプチドをさらに含む、本発明1005の方法。
[本発明1007]
前記核酸アナログが、固定化核酸(LNA)である、本発明1001の方法。
[本発明1008]
前記LNAが、カチオン性ペプチドをさらに含む、本発明1007の方法。
[本発明1009]
前記核酸アナログが、リピート領域接合部をさらに標的化する、本発明1001の方法。
[本発明1010]
前記核酸アナログが、RNAseHをリクルートする塩基を欠いている、本発明1001の方法。
[本発明1011]
伸長したトリヌクレオチドリピート領域を有するmRNAによってコードされる疾患タンパク質の、被験体中における、発現を阻害するための方法であって、該mRNAの該リピート領域を標的化する一定量の核酸アナログを該被験体へ投与する工程を含み、ここで、(i)阻害が、mRNAが伸長したトリヌクレオチドリピート領域を欠いている該疾患タンパク質の正常形態よりも該疾患タンパク質について選択的であり、かつ(ii)阻害が、該mRNAの産生に実質的に影響を与えない、前記方法。
[本発明1012]
前記リピート領域が、約125リピート以下のサイズである、本発明1011の方法。
[本発明1013]
前記疾患タンパク質が、ハンチンチン、アタキシン-3、アタキシン-1、アタキシン-2またはアトロフィン1である、本発明1012の方法。
[本発明1014]
前記核酸アナログが、約7〜約30塩基長である、本発明1011の方法。
[本発明1015]
前記核酸アナログが、ペプチド核酸(PNA)である、本発明1011の方法。
[本発明1016]
前記PNAが、少なくとも1つの修飾塩基(modifed base)を含む、本発明1015の方法。
[本発明1017]
前記修飾塩基が、[ビス-o-(アミノエトキシ)フェニル]ピロロシトシンである、本発明1016の方法。
[本発明1018]
前記PNAが、カチオン性ペプチドをさらに含む、本発明1015の方法。
[本発明1019]
前記核酸アナログが、固定化核酸(LNA)である、本発明1011の方法。
[本発明1020]
前記LNAが、カチオン性ペプチドをさらに含む、本発明1019の方法。
[本発明1021]
前記核酸アナログが、リピート領域接合部をさらに標的化する、本発明1011の方法。
[本発明1022]
前記核酸アナログが、RNAseHをリクルートする塩基を欠いている、本発明1011の方法。
[本発明1023]
前記核酸アナログを、2回以上投与する、本発明1011の方法。
[本発明1024]
前記核酸アナログを、毎週少なくとも約1回投与する、本発明1023の方法。
[本発明1025]
前記核酸アナログを、経口的に、静脈内に、動脈内に、筋肉内にまたはCNS中に投与する、本発明1011の方法。
[本発明1026]
前記核酸アナログを、脂質製剤で投与する、本発明1011の方法。
[本発明1027]
第2療法を前記被験体へ施す工程をさらに含む、本発明1011の方法。
[本発明1028]
疾患タンパク質についての伸長したトリヌクレオチドリピート領域をコードするmRNAを標的化する核酸アナログを含む物質の組成物。
[本発明1029]
前記核酸アナログが、リピート領域接合部をさらに標的化する、本発明1028の組成物。
[本発明1030]
前記核酸アナログが、約7〜約30塩基長である、本発明1028の組成物。
[本発明1031]
前記核酸アナログが、ペプチド核酸(PNA)である、本発明1028の組成物。
[本発明1032]
前記PNAが、カチオン性ペプチドをさらに含む、本発明1031の組成物。
[本発明1033]
前記核酸アナログが、固定化核酸(LNA)である、本発明1028の組成物。
[本発明1034]
前記LNAが、カチオン性ペプチドをさらに含む、本発明1033の組成物。
[本発明1035]
前記核酸アナログが、RNAseHをリクルートする塩基を欠いている、本発明1028の組成物。
[本発明1036]
前記核酸アナログが、脂質ビヒクル中に分散されている、本発明1028の組成物。
上述したように、CAG-リピート関連疾患は、正常タンパク質産生と比較しての疾患タンパク質産生の選択的阻害に関して大きな障害を示す。本発明者らによって本明細書において提示されるデータに示されるように、一本鎖核酸アナログ(NAA)は、トリプレットリピートの数の差異を活用し得、HTTまたはアタキシン-3の発現の対立遺伝子選択的阻害を達成し得る。相補的標的配列がまた突然変異mRNAおよび野生型mRNAの両方に存在したとしても、選択性は達成される。HTTについて、標的は、CAGリピート内、またはリピートとHTT遺伝子の残りとの間の3’接合部に存在し得る。アタキシン-3について、リピート、3’接合部、および5’接合部は全て、有効な標的である。阻害はロバストであり、広範囲の種々のPNAおよびLNAによって達成され得る。阻害化合物の幅広さのために、増強された効力および選択性を有する改善された薬剤の設計が可能である。
ポリグルタミン病には、翻訳されるCAGリピートの伸長によって引き起こされる遺伝性機能獲得型疾患である9つの神経変性障害が含まれる。病原タンパク質が広範囲に発現されるとしても、ニューロンの特定の集団が、各疾患においてより敏感である。ポリグルタミン疾患関連タンパク質の機能と遺伝子転写の調節とを関連付ける実質的証拠があり、ポリグルタミンタンパク質が転写に影響を与える様々な機構が提案されており、これらとしては、非常に特異的なDNA結合因子、例えば、AR(SBMA)、一般的なDNA結合タンパク質、例えば、TBP(SCA17)、Sp1、TFIIDおよびTFIIF(HD)、クロマチン構造(SCA7)、共調節因子(HD、SCA1、およびDRPLA)、ならびに恐らくユビキチン−プロテアソーム系(SCA3)の機能を変化させることが挙げられる。それらが神経機能に重要な他の生物学的プロセス、例えば、細胞内輸送(Gunawardena and Goldstein, 2005)およびミトコンドリア/エネルギー代謝(Browne and Beal, 2004)に影響を与えるという証拠も存在する。これらの障害の一部を以下においてより詳細に論じる。
ハンチントン舞踏病、大舞踏病、またはHDとも呼ばれる、ハンチントン病は、ヒョレアと呼ばれる異常な身体運動および協調の欠如を特徴とする遺伝性神経障害であり;それはまた、多数の知的能力および行動の一部の局面に影響を与える。1993年に、HDを引き起こす遺伝子が発見され、正確な検査が行なわれ得る最初の遺伝性遺伝病の1つとなった。ハンチンチンのアクセッション番号は、NM_002111である。
脊髄小脳失調症(SCA)は、歩行の緩徐進行性協調不能を特徴とし、手、発語、および眼球運動の協調不全をしばしば伴う、遺伝病のグループの1つである。頻繁に、小脳の萎縮が生じる。運動失調の他の形態と同様に、SCAは、他の症状と共に、筋肉運動の細かい協調の不全に起因する身体の不安定かつぎこちない動作を生じさせる。病気の症状は、特定のタイプ(いくつか存在する)によって、および個々の患者によって、異なる。一般的に、運動失調を有する人は、完全な知的能力を保持するが、身体的制御を次第に失い得る。
歯状核赤核淡蒼球ルイ体萎縮症(DRPLA)は、アトロフィン-1タンパク質中のポリグルタミントラクトをコードするCAGリピートの伸長によって引き起こされる常染色体優性脊髄小脳変性症である。それはまた、Haw River症候群およびNaito-Oyanagi病としても公知である。いくつかの散発性症例が、西欧諸国から報告されたが、この障害は、日本以外においては非常に稀であるようである。
A.アナログ
本発明は、標的配列へ、特に、伸長したCAGリピートを含むmRNAへハイブリダイズするそれらの能力において一本鎖オリゴヌクレオチドを模倣する核酸アナログNAAの使用を考える。NAAは、標的化および/または安定性のためにペプチドへカップリングされた分子を含む。NAAの2つの特定の例は、ペプチド核酸および固定化核酸である。
本発明は、様々な疾患関連遺伝子およびメッセージのCAGリピートを標的化する阻害性NAAの製造を考える。一般的に、NAAは、CAG/CUGリピートへ結合するか、「リピート接合部」と定義される、CAG/CUGリピートにフランキングする領域の部分およびリピートの両方へ結合する、約7〜30個の塩基の一本鎖アナログを含む。長さは、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29または30塩基長であり得る。さらに、核酸アナログは、RNAseHをリクルートする塩基を欠くように設計され得る。
本発明はまた、上述の、ポリグルタミン神経変性疾患の治療を含む。治療によって、疾患の全ての症状が扱われること、またはいかなる程度の「治癒」も達成されることは、必要ではない。むしろ、有意義な治療を達成するために、必要なことは、疾患の1つまたは複数の症状をある程度まで改善するか、有利な効果を別の療法との併用で提供するか、または疾患進行を遅らせることだけである。
以下の実施例は、本発明の好ましい態様を示すために含まれる。下記の実施例に開示される技術は、本発明の実施において十分に機能することが本発明者によって見出された技術を示し、従って、その実施についての好ましいモードを構成すると考えられ得ることが、当業者によって認識されるべきである。しかし、当業者は、本開示を考慮して、多くの変更が、本発明の精神および範囲を逸脱することなく、開示される特定の態様において成され得、それでもなお同様または類似の結果を得ることができることを認識すべきである。
オリゴヌクレオチドおよびPNA
PNA-ペプチド結合体を、Applied Biosystemsから得た試薬を使用してExpedite 8909合成機(Applied Biosystems, Foster City, CA)において合成した(Mayfield et al., 1999;Janowski et al., 2006)。PNA-ペプチド結合体を、C-18逆相HPLCによって精製し、質量分析によって評価した(Mayfield et al., 1999;Janowski et al., 2006)。LNAオリゴヌクレオチドは、Sigma-Proligo (Paris, France)から提供された。siRNAは、Integrated DNA Technologies (IDT, Coralville, IA)から購入した。
患者由来の線維芽細胞株GM04281およびGM06151をCoriell Institute (Camden, NJ)から得た。10%熱不活性化ウシ胎仔血清(Sigma)および0.5%MEM非必須アミノ酸(Sigma)が補充されたイーグル最小必須培地(MEM)(Sigma, M4655)中において、37℃および5%CO2で、細胞を維持した。細胞を、トランスフェクションの2日前に、補充MEM中において60,000細胞/ウェルで6ウェルプレート中に平板培養した。PNA-ペプチド結合体のストック溶液を使用前に5分間65℃で加熱し、形成した場合がある凝集体を溶解させた。PNA-ペプチド結合体を、OptiMEM(Invitrogen, Carlsbad, CA)を使用して適切な濃度へ希釈し、次いで細胞へ添加した。24時間後、PNA-ペプチドを含有する培地を除去し、新たな補充MEMで置き換えた。細胞を、典型的に、タンパク質アッセイのためにトランスフェクションの4日後に採取した。siRNAまたはLNAを、製造業者の指示に従ってRNAiMAX(Invitrogen)を使用して細胞へトランスフェクションした。好適な量の脂質(100 nMオリゴヌクレオチドについて3μL)を、オリゴヌクレオチド含有OptiMEMへ添加し、オリゴヌクレオチド−脂質混合物(250μL)を20分間インキュベートした。OptiMEMを1.25 mLの最終体積まで混合物へ添加し、次いで細胞へ添加した。培地を24時間後に新たな補充MEMと交換した。
細胞をトリプシン-EDTA溶液(Invitrogen)で採取した。各サンプル中のタンパク質濃度を、BCAアッセイ(Thermo Scientific, Waltham, MA)で定量した。SDS-PAGE(分離ゲル:5%アクリルアミド-ビスアクリルアミド/34.7:1、450 mM Tris-アセテート pH 8.8;濃縮ゲル:4%アクリルアミド-ビスアクリルアミド/34.7:1、150 mM Tris-アセテート pH 6.8)(XT Tricine Running Buffer, Bio-rad, Hercules, CA)を使用し、野生型および突然変異HTTタンパク質を分離した。ゲルを、70Vで15分間、続いて100Vで4時間、泳動させた。電気泳動装置を氷水浴中に配置し、ランニングバッファーの過熱を防止した。本発明者らは、各レーンにおけるタンパク質上の同等のローディンを確実にするために、アクチンタンパク質の発現をモニタリングした。
CAGリピートの数を、GeneBankにおける公開されたmRNA配列に従って評価した。TATAボックス結合タンパク質(TBP)(約19個のCAGリピート、NM_003194)、AAK1(6個のCAGリピート、NM_014911)、およびPOU3F2(約6個のCAGリピート、NM_005604)。タンパク質溶解物をSDS-PAGE(7.5%アクリルアミドプレキャストゲル;Bio-Rad)によって分析した。抗TBP抗体(1:2000;Sigma)、抗AAK1抗体(1:1000;Abcam, Cambridge MA)、抗POU3F2抗体(1:1000;Abnova, Taipei, Taiwan)。
YAC128マウス(FVBN/NJバックグラウンド株)を、Jackson Labs(ストック番号004938)から得た。雄性YAC128マウスを野生型(WT)雌性FVBN/NJマウスと交配し、P1-P2の仔を採取し、PCRによって遺伝子型決定した。線条体中型有棘ニューロン(MSN)の初代培養物を、YAC128およびコントロール野生型の仔から樹立した。線条体を切開し、刻み、トリプシンで消化した。分離後、ニューロンを、2%B27、1 mMグルタミンおよびペニシリン-ストレプトマイシン(全てInvitrogen製)が補充されたNeurobasal-A培地中のポリ-L-リジン(Sigma)コート12 mm円形カバーガラス(Assistent)上に平板培養し、37℃で5%CO2環境中にて維持した。PNAを9-DIV(デイズ・インビトロ)MSNへ添加した。13-DIV MSNを、培養培地へ添加されたNeurobasal-A中の250μMグルタマートへ7時間曝露した。グルタマートでの処理直後に、ニューロンを、PBS(pH7.4)中4%パラホルムアルデヒドおよび4%スクロース中において30分間固定し、0.25%Triton-X-100中において5分間透過処理し、DeadEnd蛍光定量TUNELシステム(Promega)を使用することによって染色した。核を5μMヨウ化プロピジウム(propidium iodine)(PI)(Molecular Probes)で対比染色した。カバーガラスをPBSで広範囲に洗浄し、Mowiol 4-88(Polysciences)上に載せた。定量化のために、各々100〜300個のMSNを含有する、6〜8個の無作為に選択した顕微鏡視野を、YAC128および野生型培養物について細胞カウントした。TUNEL陽性ニューロン核の数を、各顕微鏡視野中のPI陽性ニューロン核のフラクションとして計算した。各顕微鏡視野について測定されたTUNEL陽性核のフラクションを平均し、結果を平均値±SEとして示す(n=カウントされた視野の数)。MSN細胞は周囲のグリア細胞によって培養物中において支持されていたが、MSN細胞のみを神経保護アッセイの間カウントした。
処理および未処理線維芽細胞からのトータルRNAを、トランスフェクションの3日後にTRIzol(Invitrogen)を使用することによって抽出した。次いで、各サンプルを、25℃で10分間、DNase Iで処理した。逆転写反応を、製造業者のプロトコルに従ってHigh Capacity Reverse Transcription Kit(Applied Biosystems)を使用して行なった。定量的PCRを、iTaq SYBR Green Supermix(Bio-rad)を使用して7500リアルタイムPCRシステム(Applied Biosystems)において行なった。データを、GAPDH mRNAのレベルに対して標準化した。HTTについて特異的なプライマー配列は、以下の通りである:フォワードプライマー、
リバースプライマー、
GAPDHについて特異的なプライマーは、Applied Biosystemsから得られる。
本発明者らは、mRNA一次配列ではなくmRNA二次構造中の差異を識別する一本鎖オリゴマーを使用して選択性を達成することが可能であり得ると仮定した。コンピューター予測、NMRおよびフットプリンティングアッセイは、RNA内のトリプレットリピート配列がヘアピン構造を形成することを示している(図1A)(Sobczak et al., 2003;Gacy et al., 1995)。野生型および突然変異mRNAによって形成される構造は、異なるエネルギーおよび安定性を有し、突然変異対立遺伝子の選択的認識および突然変異タンパク質発現の選択的阻害を恐らく可能にする。
PNAをN→C末端で列挙する。siRNA(アンチセンス鎖のみ)およびLNAを5’→3’で列挙する。D-アミノ酸が全てのペプチド結合体において使用される。ミスマッチの塩基に下線が引かれている。LNAについて、修飾塩基を大文字として示し、DNA塩基は小文字である。
PNAをN→C末端で列挙する。全てのPNAは、N末端に1個のD-リジンおよびC末端に8個のD-リジンを有する。PhpC塩基(X)に下線が引かれている。Tm測定は相補的RNAオリゴマーを使用した。ミスマッチコントロールPNA GCCACTACTGATAを比較のために使用した。
Claims (22)
- 伸長したCAGリピート領域を有するmRNAによってコードされる疾患タンパク質の発現を阻害するための医薬の製造における、該タンパク質をコードする領域内の該mRNAの該リピート領域を標的化する、ペプチド核酸(PNA)または固定化核酸(LNA)である核酸アナログの使用であって、
ここで、(i)阻害が、mRNAが伸長したCAGリピート領域を欠いている該疾患タンパク質の正常形態よりも該疾患タンパク質について選択的であり、かつ(ii)阻害が、該mRNAのレベルを低下させず、
該核酸アナログが、該mRNAの該CAGリピート領域と相補的な配列を含み、かつ該疾患タンパク質の発現を阻害する、
前記使用。 - 前記リピート領域が、125リピート以下のサイズである、請求項1記載の使用。
- 前記疾患タンパク質が、ハンチンチン、アタキシン-3、アタキシン-1、アタキシン-2またはアトロフィン1である、請求項2記載の使用。
- 前記核酸アナログが、13〜30塩基長である、請求項1〜3のいずれか一項記載の使用。
- 前記核酸アナログが、前記mRNAのCAGリピート領域の少なくとも2、3、4、5、6、またはそれより多いリピートと相補的な配列を含む、請求項1〜4のいずれか一項記載の使用。
- 前記PNAまたはLNAが、カチオン性ペプチドをさらに含む、請求項1〜5のいずれか一項記載の使用。
- 前記核酸アナログが、リピート領域接合部をさらに標的化する、請求項1〜6のいずれか一項記載の使用。
- 前記核酸アナログが、RNAseHをリクルートする塩基を欠いている、請求項1〜7のいずれか一項記載の使用。
- 伸長したCAGリピート領域を有するmRNAによってコードされる疾患タンパク質の発現を阻害するための薬学的組成物であって、該タンパク質をコードする領域内の該mRNAの該リピート領域を標的化する、ペプチド核酸(PNA)または固定化核酸(LNA)である核酸アナログを含み、
ここで、(i)阻害が、mRNAが伸長したCAGリピート領域を欠いている該疾患タンパク質の正常形態よりも該疾患タンパク質について選択的であり、かつ(ii)阻害が、該mRNAのレベルを低下させず、
該核酸アナログが、該mRNAの該CAGリピート領域と相補的な配列を含み、かつ該疾患タンパク質の発現を阻害する、
前記薬学的組成物。 - 前記リピート領域が、125リピート以下のサイズである、請求項9記載の薬学的組成物。
- 前記疾患タンパク質が、ハンチンチン、アタキシン-3、アタキシン-1、アタキシン-2またはアトロフィン1である、請求項10記載の薬学的組成物。
- 前記核酸アナログが、13〜30塩基長である、請求項9〜11のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、前記mRNAのCAGリピート領域の少なくとも2、3、4、5、6、またはそれより多いリピートと相補的な配列を含む、請求項9〜12のいずれか一項記載の薬学的組成物。
- 前記PNAが、少なくとも1つの修飾塩基(modifed base)を含む、請求項9〜13のいずれか一項記載の薬学的組成物。
- 前記PNAまたはLNAが、カチオン性ペプチドをさらに含む、請求項9〜14のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、リピート領域接合部をさらに標的化する、請求項9〜15のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、RNAseHをリクルートする塩基を欠いている、請求項9〜16のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、2回以上投与されるように用いられることを特徴とする、請求項9〜17のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、毎週少なくとも1回投与されるように用いられることを特徴とする、請求項18記載の薬学的組成物。
- 前記核酸アナログが、経口的に、静脈内に、動脈内に、筋肉内にまたはCNS中に投与されるように用いられることを特徴とする、請求項9〜19のいずれか一項記載の薬学的組成物。
- 前記核酸アナログが、脂質製剤の形態である、請求項9〜20のいずれか一項記載の薬学的組成物
- 第2療法と併用される、請求項9〜21のいずれか一項記載の薬学的組成物。
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AU2017216467A1 (en) | 2017-08-31 |
EP2317847A4 (en) | 2014-10-15 |
WO2010014592A1 (en) | 2010-02-04 |
EP2317847A1 (en) | 2011-05-11 |
AU2009276763A1 (en) | 2010-02-04 |
EP2317847B1 (en) | 2019-04-17 |
CA2732343C (en) | 2017-05-09 |
US20110190222A1 (en) | 2011-08-04 |
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JP2015171368A (ja) | 2015-10-01 |
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