JP5852557B2 - 新規抗老化剤及びそれらを同定する方法 - Google Patents
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Description
本願は出願日が2009年4月10日である米国仮出願第61/168,311号及び出願日が2009年4月10日である米国仮出願第61/168,335号の35U.S.C.§119(e)の権利を主張し、それら全体で参照として組み込まれる。
本発明は、新規抗老化剤、これら薬剤を検出又は同定する新規方法、及びそのように同定される抗老化剤の加齢に伴う病気の予防及び/又は治療への使用iに関する。また、本発明は、生物試料における抗老化剤の抗老化生物濃度を測定する新規方法を関する。特に、本発明は、各種の加齢に伴う病気を予防又は治療するためのカロリー制限を模倣する抗老化剤として低用量のラパマイシン又はその類似物、他のラパマイシンの標的(TOR)阻害剤の使用を紹介する。
カロリー制限(CR)は、酵母ないし哺乳類の老化速度を遅らせる最も実用的な方法として認められていました。カロリー制限は、加齢に伴う病気(例えば霊長類モデルにおけるパーキンソン病(Maswood,N.等,Proc.Natl.Acad.Sci.USA,101:18171-6(2004)、アルツハイマー病(Qin,W.等,J.Alzeheimer’s Dis.,10:417-422(2006)、Dahl-SSラットモデルにおける高血圧及び心臓障害(Seymour,E.M.等,J.Mol.Cell Cardiol.,41:661-668(2006)、線維症(Castello,L.等, FASEB J.,19:1863-1865(2005)、及び腎臓病(Yu, B.P.等/J.Gerontol.,37:130-141(1982))の発生率を低下させる又は発症を遅らせることが示されてきました。カロリー制限もさまざまな自然発生腫瘍を抑制するかつ人間乳房、結腸及び前立腺の癌の発生を減少させる(Platz,E.A.,J.Nutr.,132:3471S-81S(2002);Steinbach,G.等,Cancer Res.,54:1194-1197(1994); Michels, K.B.等,JAMA,291:1226-30(2004)に概説された。
糸粒体は酸化的リン酸化の過程により代謝燃料(例えば、グルコース及び脂肪酸)を利用可能な形のエネルギーであるアデノシン5’-三リン酸(ATP)に変換することに関与する細胞器官である。糸粒体は適切な細胞機能にとって重要な他の過程(カルシウム恒常性、細胞内情報伝達、及びアポトーシスの制御を含む)に関与する。
テロメアは染色体の端に多くのGを含む繰り返しDNA配列だ。テロメアはテロメア結合タンパク質を通じて固定して自然発生の二本鎖DNA切断(DSB)の過程に識別されない。
本発明は抗老化剤を同定・検出・純化するための新規方法及び加齢に伴う病気の予防及び治療ための薬剤の使用を説明する。本発明は次の発見に基づいて:(1)酵母において、栄養素信号がAMPK後続のミトコンドリア経路でテロメア機能不全により誘発される細胞周期停止状態を延長することを抑制する;(2)第一のヒト線維芽細胞において、低用量のラパマイシン、グルコース制限及びAMPK活性化因子がミトコンドリア機能を刺激するかつテロメア機能不全により誘発される細胞周期停止状態を延長する;(3)いくつかの抗老化及び癌化学予防剤も酵母及びヒト細胞においてミトコンドリア機能を刺激するかつ老化細胞の減少を抑制する;(4)多くの加齢に伴う病気が糸粒体及び/又はテロメアの機能不全に関与する;及び(5)低用量のラパマイシンが急性心筋虚血性梗塞及びに虚血性脳損傷を予防する、MPP+により誘発されるROS増加を制される、培養された神経細胞の寿命と腫瘍細胞形質転換を抑制する。
(i)テロメア機能不全又はDNA損傷による細胞周期が停止された条件で化合物又は組成物を酵母細胞で培養する;
(ii)アポトーシスアッセイを使って死亡酵母細胞の集団を測定する、あるいは、
(iii)細胞周期が停止された条件を取り除き、生き残った細胞の数を測定する、及び
(iv)段階(ii)で得られた死細胞の集団又は段階(iii)で得られた生き残った細胞の数を対照実験と比較する、対照実験で上述化合物又は組成物を含まない以外に、段階(i)と同じ条件である。
そのうち、対照実験に対して、(ii)で得られた死亡酵母細胞減少個体群あるいは、段階(iii)で得られた生き残った細胞数が、ただしこの化合物又は組成物が候補抗老化剤のであることを示した。
(i)検出した化合物又は組成物を培養を細胞周期停止状態にあった哺乳類細胞とある期間で培養して;
(ii)生き残った老化細胞の集団を測定する;及び
(iii)段階(vi)の生き残った哺乳類の老化細胞の集団を対照実験で得られた生き残った老化細胞の集団と比較する。
そのうち、対照実験に対して、生き残った老化細胞集団が増えると、ただし、この化合物又は組成物が候補抗老化剤のであることを確認する。
(i)出した化合物又は組成物を正常状態ヒト細胞株とある期間で培養して;
(ii)ミトコンドリア量、ミトコンドリアDNA含量、又はミトコンドリア 転写因子の発現を測定することによって、ヒト細胞のミトコンドリア生合成を測定する;及び
(iii)対照実験の結果と比較し、結果を得る、
そのうち、段階(ii)でのミトコンドリア生合成を増強すれば、ただし、さらに同定した化合物又は組成物が候補抗老化剤であることを確認する。
(i)生物試料を溶媒で希釈する;
(ii)テロメア機能不全又はDNA損傷により酵母細胞の細胞周期が停止された条件で希釈された試料を変異酵母細胞で培養する;
(iii)細胞周期が停止された条件を取り除き、生き残った酵母細胞の数を測定する;及び、
(iv)段階(iii)で得られた生き残った細胞の数を培養段階(ii)と同じ条件で対照実験における生き残った細胞の数と比較する、ただし、対照実験には上述の生物試料を含まない。
そのうち、対照実験に対して段階(iii)で得られた生き残った細胞数が増加すると、生物試料が抗老化剤を含むことを示唆する。
(i)被験者の生物試料を溶媒で希釈する;
(ii)テロメア機能不全又はDNA損傷により酵母細胞の細胞周期が停止された条件で、希釈された生物試料を変異酵母細胞で培養する;
(iii)細胞周期が停止された条件を取り除き、生き残った酵母細胞の数を測定する;
(iv) 段階(iii)得られた生き残った細胞の数を培養段階(ii)と同じ条件で対照実験で生き残った細胞の数と比較する、ただし、対照実験には上述の生物試料を含まない;及び
(v)生き残った酵母細胞の数を抗老化剤の濃度と生き残った酵母細胞の数との事前準備された標準方程式又は標準曲線に代して、抗老化剤の生物濃度を計算する。
(vi)異なる既知濃度の精製抗老化剤を有する複数の標準溶液を調製する、この標準溶液が被験者の生物試料を培養する溶媒を用いられる;
(vii)テロメア機能不全又はDNA損傷を起こし、さらに細胞周期停止された条件で、標準溶液を変異酵母細胞と培養する。
(viii)細胞周期が停止された条件を取り除く、それぞれの培養した標準溶液で生き残った酵母細胞の数を測定する;及び
(ix)段階(viii)で得られた生き残った細胞の数をその対応する抗老化剤の濃度に対してプロットして、標準曲線を得る、及び/又は標準方程式を得る。
本明細書で用いられている用語「a」、「an」及び「the」に対して、特別な注記がなければ、単数と複数も指す。
本発明は後述する各種の発見に基づくものである。
ほとんどの癌細胞はミトコンドリア機能不全を示す。この現象がワーブルグ効果と呼ばれ、すなわち癌細胞において、60%にも達するATPが好気条件下で解糖によって生成され、一方、正常細胞において、多数のATPがミトコンドリア酸化的リン酸化によって生成される。発癌性転化は酸化的リン酸化を抑制し且つ解糖を増加でき、腫瘍抑制タンパク質p53は酸化的リン酸化に対して上方調節し且つ解糖に対して抑制することがすでに示された。しかしながら、影響を受けたミトコンドリア機能が癌の原因か結果かはまだ明確されなかった。
広範囲な研究にもかかわらず、神経変性疾患の機序が不明である。ミトコンドリア機能不全は疾患に役割を果たすかもしれない。原因はPakin(パーキンソン病に関わる)、Huntintin(ハンチントン病に関わる)及びアミロイド-β(アルツハイマー病を引き起こす老人斑)は共にトコンドリア機能に関与することにある。最近の研究も自食作用(タンパク質分解)がこれら疾患で役割を果たすことを示唆する。
テロメア機能不全が慢性心不全に重要な役割を果たすことが示された。さらに、培養された心筋細胞において、TRF2機能を干渉することはテロメア浸食及びアポトーシスを引き起こすことが示された。逆に、外因性TRF2が保護され、酸化的ストレスを防止することができるが、それによって、例え有糸分裂後、非周期細胞においても、依然テロメア機能不全によって細胞死を発生することができることを表明した(Oh,H.等,Proc.Natl.Acad.ScL USA,100:5378-5383(2003))。体内において、第5代TERC−欠損マウス(G5TERC−KO)(TERC遺伝子コード化テロメラーゼRNAの欠損によるテロメラーゼ変異体モデル)は心筋細胞における短いテロメア、心筋心室拡張、心筋の薄化、心臓の機能不全、及び突然死を著しく表した。G5TERC−KOマウスの心臓試片は、野生型マウスに比べて、DNA損傷応答タンパク質p53の発現が増加され、アポトーシスが増加され、及び左心室筋細胞数が50%減少されることを示した(Leri,A.等,EMBO J.,22:131-139(2003))。
加齢性黄斑変性(AMD)は老人(>50歳)の失明の主な原因である。それは網膜色素上皮細胞(RPE)の退化から始め、且つ最終に視野の中心(黄斑)の視力喪失に至る。報告によると、テロメア浸食、ミトコンドリア機能喪失及び細胞消失が共にこの疾患と関わる(Matsunaga,H.,Invest.Ophthalmol.Vis.ScL,40:197-202(1999);Liang,F.Q.等,Exp.Eye Res.,76:397-403(2003))。そこで、ミトコンドリア機能を改善し、それによって、テロメア浸食により誘発される細胞消失を予防することは、病気の初期段階を予防又は安定化することができる。興味深いことに、50pMの低用量のラパマイシンの、この疾患を治療する用途に対しては、すでに特許を出願した(米国特許第7,083,802号)。従って、テロメア機能不全により誘発される老化モデルは、AMDを予防又は治療する薬剤候補の選択に用いられることができる。
変形性関節症(OA)の特徴は関節軟骨の進行性消失であり、老人個体群における最もよく見られる慢性の関節疾患であり、著しい疼痛及び身体障害を引き起こす。軟骨細胞の機能は適切な軟骨基質の維持にとって必要である。テロメア機能不全、ミトコンドリア変異及び軟骨細胞におけるアポトーシス式の細胞死はOAと関わることがすでに示された(Martin,J.A.等,J.Bone Joint Surg.Am.,85−A Suppl.2:106-110(2003); Ruiz−Romero,C等,MoI.Cell Proteomics.,8:172-189(2009);Dave,M.等,関節炎Rheum.,58:2786-2797(2008))、これは、軟骨細胞におけるテロメア機能不全による細胞消失が潜在の疾患発症の機序になっていることを表明する。そこで、ミトコンドリア機能を改善して、それによってテロメア機能不全により誘発される細胞消失を予防するのは、疾患の早期を予防又は安定させることができる。従って、テロメア機能不全により誘発される老化モデルはOAを予防又は治療する薬剤候補の選択に用いられることができる。
特発性肺線維症(IPF)は慢性の進行性間質性肺疾患であり、特徴は肺間質の線維性組織の異常及び過剰沈積にある。該疾患は通常50歳以上年齢の患者に発生する。最近、テロメラーゼの変異が成人発症の肺間質線維症に至り(Tsakiri,K.D.等人,Proc.Natl.Acad.Sci.USA,104:7552-7557(2007))、且つ短いテロメアがIPFと関係がある(Alder,J.K.等, Proc.Natl.Acad.Sci.USA,105:13051-13056(2008);Armanios,M.Y.等,N Engl.J.Med.,356:1317-1326(2007))ことが示された。証明によると、肺上皮細胞における糸粒体及びアポトーシスがIPFと関わる(Kuwano,P.,Intern.Med.,47:345−353(2008))。これらの結果はテロメア機能不全による肺上皮細胞の減少は加齢性のIPFの初期起因であるかもしれないことを表明する。そこで、ミトコンドリア機能を改善し、それによって肺上皮細胞におけるテロメア浸食より誘発される細胞減少を予防することは、病気の初期段階を予防または安定化させる可能性がある。従って、テロメア機能不全により誘発される老化モデルはAMDを予防又は治療する薬剤候補の選択に用いられることができる。
線維芽細胞の老化が皮膚老化の兆候(例えば、しわ)に好適な役割を果たす。テロメアの進行性短縮及び活性酸素種又はUVによるDNA損傷の蓄積は、線維芽細胞老化及び後続の細胞消失を含む線維芽細胞老化を引き起こす。次に、線維芽細胞老化は、増殖性能減少(Mine,尾S.等,PLoS ONE,3[12]:e4066(2008);Hayflick,L./Invest.Dermatol.,73:8−14(1979))、細胞形態及び新陳代謝の変化、細胞外のマトリックスタンパク質(例えば1型及び3型膠原質)の産生の減少(Varani,J.等,Am.J.Pathol.,168:1861-1868(2006))、及び細胞外基質の退化に関わるプロテアーゼの過剰発現(West,M.D.等,Exp.Cell Res.,184:138-147(1989))を含む機能低下をもたらす。これらの体外変化は共に多少程度に加齢に伴う皮膚の体内変化と関与する。機能性のミトコンドリア個体群を維持することはテロメア短縮を遅延するだけでなく(図9B)、機能性を依然有する老化線維芽細胞の減少を予防し(図7及び図9A)、且つそれによって皮膚の老化を遅延し、及び皮膚癌を予防する。
機能障害性テロメア及びミトコンドリア変異がRAにおける潜在的な病原因子である。関節リウマチ患者の造血前駆細胞(HPCs)及び骨髄間葉幹細胞(MSCs)は早過ぎのテロメア短縮及び減らされた複製能を表すことがすでに表明された(Colmegna,I.等,関節炎 Rheum.,58:990-1000(2008);Kastrinaki,M.C.等,Ann.Rheum.Dis.,67:741-749(2008))。また、この疾患の主要な感受性遺伝子とするHLA−DRB1*04対立遺伝子はテロメア短縮の過程に対して調節できることがすでに表明された(Schonland,S.O.等,Proc.Natl.Acad.ScL USA,100:13471-13476(2003))。いくつかの研究も、RAにおける炎症を起こした滑膜の組成及び構造方面の一部の特徴的な変化は、滑膜細胞がすでに変化したアポトーシス応答と関わることを表明した(Korb,A.等,アポトーシス,14:447-454(2009))。また、対照に比べて、RAによる滑膜細胞のmtDNAの変異が大幅に増える(Da Sylva,T.R.等,関節炎 Res.Ther.,7:R844-851(2005))。従って、ミトコンドリア機能を改善し、且つテロメア短縮により誘発される細胞死を予防する薬剤候補を研究・開発して、この疾患の治療に用いられることができる。
糖尿病とは高血糖値を至ることができる疾患を指し、原因はインスリン産生の減少(1型糖尿病)またはインスリンの効果に対して生成した抵抗性(2型糖尿病及び妊娠期間)にある。テロメア機能不全又はミトコンドリア機能不全によって、β-細胞機能が早すぎて消失することは糖尿病の初期段階であるかもしれない。広範に受け取られる観点としては、mtDNA欠陥が糖尿病の病因の1つのよくある要因であり、且つmtDNAの再配列(Ballinger, S.W.等,Nat.Genet.,7:458-459(2004);Ballinger,S.W.等,Nat.Genet., 1:11-15(1992))及びtRNAの変異(van den Ouweland,J.M.等,糖尿病,43:746-751(1994))は糖尿病と関わる。また、マウスの膵臓β細胞において、ミトコンドリア生合成のそのうちの1つのの主要タンパク質のミトコンドリア転写因子TFAMに対して不活化を行うことは、血清インスリンの激しい減少及び空腹及び非空腹状態での血中グルコースの増加をもたらす(Koster,J.C.等,Cell,100:645-654(2000);Wallace,D.C.,Am.J.Med.Genet.,106:71-93(2001))。それ以外に、ヒト膵島におけるβ-細胞は体外においてテロメア浸食及びテロメアによる老化を受けることを表明した(Halvorsen,T.L./Endocrinol,166:103-109(2000))。そこで、ミトコンドリア機能を改善し且つテロメア浸食により誘発される細胞消失を予防することができる薬剤候補はこの疾患の予防に用いられることができる。
A.テロメア機能不全モデルを使用してハイスループット・スクリーニングを行って加齢に伴う病気を予防又は治療する抗老化候補を同定及び検出する。
ACAGCTAACTCCAAGTCAGATTATGTC−3’及び
5’−GTAGACACTTGAGACT AACAACCGT−3’、
並びに、βアクチン(対照群)のプライマー・プローブセット
5’−CAAAGACCTGTACGCCAACACAGT−3’及び
5’−TTGCTGATCCACATCTGCTGGAAG5−3’
は、50pMラパマイシン及びその他の薬剤によるTFAM mRNAの向上を測定するのに成功裏に使用されてきたものだが(データ示さず、Fu X, et al,PLoS ONE,3(4):e2009,2008参照)、これらもまた使用され得る。TFAM mRNAを約2倍増加させることができる化合物又は組成物は陽性と認められ、さらにcdcl3−l又はWI−38テロメア機能不全モデルにおいて老化維持が測定される。
特定のTOR阻害剤ラパマイシン(シロリムス)は、CCI779(テムシロリムス)、RAD−001(エベロリムス)、AP−23573(デホロリムス)、AP−23675、AP−23841、ABT−578(ゾタロリムス)、7-エピ-ラパマイシン、7-チオメチル-ラパマイシン、7-エピ-トリメトキシフェニル-ラパマイシン、7-エピ-チオメチル-ラパマイシン、7-デメトキシ-ラパマイシン、32- デメトキシ-ラパマイシン、2-デスメチル-ラパマイシン、及び42-O-(2-ヒドロキシル)エチル−ラパマイシンを含む大環状トリエン分子の初期成員である。ラパマイシンは抗真菌活性を有することが一番早めに発見された(Vezina, C.等,J.Antibiot.,28:721(1975);Sehgal,S.N.等,J.Antibiot.,28:727(1975);Baker,H.A.等,J.Antibiot.,31:539(1978);米国特許第3,929,992号、及び米国特許第3,993,749号)。
Claims (8)
- 加齢に伴う病気を予防又は治療する薬剤を同定又は検出するための方法であって、
細胞周期停止状態モデル又は分裂終了細胞モデルとして、機能障害性テロメアを含む変異酵母の一種であるcdc13−1を用いて、1種類以上の化合物又は組成物をスクリーニングしてそれらの抗老化作用を監視するものであり、
前記スクリーニングは、
(i) テロメア機能不全により細胞周期が止められた条件のもとで化合物又は組成物を酵母細胞と培養する工程と、
(ii)
(iii) 培養の温度を低下させることにより細胞周期が止められる条件を取り除き、生き残った細胞の数を測定する工程と、
(iv) 前記工程(iii)で得られた生き残った細胞の数を、前記工程(i)と同じ条件の下、しかし前記化合物又は組成物の不存在下の対照実験で得られた生き残った細胞の数と比較する工程と、
を含み、
前記対照実験との比較で、前記工程(iii)で得られた生き残った細胞の数の増加は、その培養された化合物又は組成物が抗老化剤の候補であることを示すものである、ことを特徴とする、加齢に伴う病気を予防又は治療する薬剤を同定又は検出するための方法。 - 抗老化作用が、
(a)老化細胞又は分裂終了細胞における細胞周期停止状態の悪化を防ぐこと、
(b)ミトコンドリア機能を刺激、改善または維持すること、
(c)ミトコンドリア又はテロメアの機能喪失に関連する加齢に伴う病気を予防すること、又は、
(d)活性酸素種(ROS)の増大又はテロメア機能不全によって誘発されるアポトーシス死の増加を防ぐこと、
から選ばれるものである、請求項1に記載の方法。 - 請求項1又は2に記載の方法であって、加齢に伴う病気(疾患または障害)が、異常増殖性疾患、変性疾患、または機能低下疾患である、方法。
- 請求項1に記載の方法であって、
(v) 同定される化合物又は組成物を一定時間、哺乳類の老化細胞と培養する工程と、
(vi) 生き残った老化細胞の個体群を測定する工程と、
(vii) 前記(vi)の生き残った哺乳類の老化細胞の個体群を、対照実験で得られた生き残った老化細胞の個体群と比較する工程と、
を更に含み、
前記対照実験との比較で、生き残った哺乳類の老化細胞の個体群の増加は、前記哺乳類の老化細胞と共に培養された化合物又は組成物が抗老化剤の候補であることを確認するものである、方法。 - 請求項4に記載の方法であって、
(viii) 同定される化合物又は組成物を一定期間、正常増殖ヒト細胞と培養する工程と、
(ix) ミトコンドリア質量、ミトコンドリアDNA含量、又はミトコンドリア転写因子の発現を測定することによってヒト細胞のミトコンドリア生合成を測定する工程と、
(x) 前記工程(ix)の結果を対照実験の結果と比較する工程と、
を更に含み、
対照実験と比べて前記工程(ix)で得られたミトコンドリア生合成の増進は、同定された化合物又は組成物が抗老化剤の候補であることを更に確認する、方法。 - 請求項1〜3のいずれか一項に記載の方法であって、
(i) 前記化合物又は組成物を含む生物試料を溶媒で希釈する工程、
(ii) テロメア機能不全により酵母細胞の細胞周期が止められた条件の下で前記希釈された試料を変異酵母細胞と培養する工程、
(iii) 細胞周期が止められる条件を取り除くと共に、生き残った酵母細胞の数を測定する工程、及び、
(iv) 工程(iii)で得られた生き残った細胞の数を、培養工程(ii)と同じ条件での対照実験(但し、その対照実験では前記の生物試料の化合物又は組成物を含まない)において生き残った細胞の数と比較する工程、を含み、
前記対照実験での生き残り細胞数と比較して前記工程(iii)で得られた生き残り細胞の数が増えていることは、前記生物試料が抗老化剤を内包することを示唆するものである、ことを特徴とする方法。 - 請求項1〜3のいずれか一項に記載の方法であって、
(i) 前記化合物又は組成物を含む生物試料を溶媒で希釈する工程、
(ii) テロメア機能不全により酵母細胞の細胞周期が止められた条件の下で前記希釈された試料を変異酵母細胞と培養する工程、
(iii) 細胞周期が止められる条件を取り除くと共に、生き残った酵母細胞の数を測定する工程、
(iv) 工程(iii)で得られた生き残った細胞の数を、培養工程(ii)と同じ条件での対照実験(但し、その対照実験では前記の生物試料の化合物又は組成物を含まない)において生き残った細胞の数と比較する工程、
(v) 対象となる生物試料を希釈するために使われた溶媒を用いて、異なる既知濃度の精製抗老化剤を有する複数の標準溶液を調製する工程、
(vi) 上記の(ii)から(iv)の各工程を繰り返す工程、
(vii) 工程(vi)で得られた生き残り細胞数をその対応する抗老化剤濃度に対してプロットして、標準方程式及び/又は標準曲線を得る工程、
(viii) 工程(iv)で得られた生き残った酵母細胞の数を、工程(vii)で得られた抗老化剤の濃度と生き残り酵母細胞の数との間の予め確立された標準方程式又は標準曲線にあてはめて、抗老化剤の生物学的濃度を計算する工程、
を含むことを特徴とする方法。 - 請求項1に記載の方法であって、当該方法は更に、
栄養素、TOR、AMPK、ミトコンドリア、老化経路のうちの少なくとも一つの構成成分に対して当該方法で同定される薬剤の活性を測定すること、を含み、
但し、前記薬剤は、
(a) 老化もしくは分裂終了細胞において細胞周期停止状態を維持する、
(b) ミトコンドリアの劣化を防止する、
(c) 老化もしくは分裂終了細胞において細胞周期停止状態の劣化を防止する、又は、
(d) 老化悪化に続く異常増殖もしくは細胞死を防止する、
ことを特徴とする方法。
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WO2010118419A4 (en) | 2011-04-21 |
CN104997774A (zh) | 2015-10-28 |
EP2416792A4 (en) | 2012-10-24 |
JP2012523239A (ja) | 2012-10-04 |
JP5931164B2 (ja) | 2016-06-08 |
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WO2010118419A3 (en) | 2011-02-17 |
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KR20120061081A (ko) | 2012-06-12 |
US20170027914A1 (en) | 2017-02-02 |
EP2416792A2 (en) | 2012-02-15 |
CN102612564B (zh) | 2015-08-26 |
KR20130128018A (ko) | 2013-11-25 |
EP2965763A9 (en) | 2016-03-02 |
WO2010118419A2 (en) | 2010-10-14 |
AU2010233073A1 (en) | 2011-12-01 |
EP2965763B8 (en) | 2018-08-15 |
JP2015091237A (ja) | 2015-05-14 |
EP2965763A1 (en) | 2016-01-13 |
US20230338343A9 (en) | 2023-10-26 |
EA201101488A1 (ru) | 2012-07-30 |
US9360471B2 (en) | 2016-06-07 |
EA023244B1 (ru) | 2016-05-31 |
US8492110B2 (en) | 2013-07-23 |
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