JP5485146B2 - α−ENaC発現のRNAi阻害 - Google Patents
α−ENaC発現のRNAi阻害 Download PDFInfo
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- JP5485146B2 JP5485146B2 JP2010511658A JP2010511658A JP5485146B2 JP 5485146 B2 JP5485146 B2 JP 5485146B2 JP 2010511658 A JP2010511658 A JP 2010511658A JP 2010511658 A JP2010511658 A JP 2010511658A JP 5485146 B2 JP5485146 B2 JP 5485146B2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
説明を容易にするため、「ヌクレオチド」または「リボヌクレオチド」とは、本明細書では、RNA剤の1個以上のモノマーサブユニットを指して用いられる場合がある。本明細書において用語「リボヌクレオチド」または「ヌクレオチド」の使用は、修飾RNAまたはヌクレオチドサロゲートの場合、以下にさらに記載される通り、修飾ヌクレオチド、または、1個以上の位置のサロゲート置換部分も指す。
本明細書において「α−ENaC発現に関連する障害」とは、(1)α−ENaCの存在により少なくとも部分的に媒介され、また、(2)その転帰がα−ENaC存在のレベルを低下させることにより影響を受け得る何らかの生物学的または病理学的状態を指す。α−ENaC発現に関連する特定の障害を以下に示す。
本発明の処置は対症的または予防的であり得る。
上述の通り、本発明は、α−ENaCの阻害剤として有用なsiRNAを同定するための系を提供する。上述の通り、shRNAは細胞内でプロセシングされてshRNAの基幹構造と同じ配列を有する二本鎖部分を有するsiRNAをもたらすため、この系はα−ENaCの阻害剤として有用なshRNAを同定するのにも等しく有用である。説明のために、この章ではsiRNAについて述べるが、この系は対応するshRNAも包含する。具体的には、本発明は、α−ENaC活性の阻害を標的とするsiRNAの作製の成功を示す。本明細書に記載されている技術および試薬は、他の遺伝子または遺伝子領域を標的とする可能性のある新規なsiRNAを設計するために容易に適用し、本明細書に記載の通りα−ENaCの阻害におけるそれらの活性を試験することができる。
候補iRNA剤は、安定性、例えば、そのiRNA剤が対象の体内に導入されたときなどのエンドヌクレアーゼまたはエキソヌクレアーゼによる切断に対するその感受性に関して評価することができる。修飾、特に切断、例えば対象の体内に見られる成分による切断に対して感受性のある部位を同定するための方法を使用することができる。このような方法は、例えば血清、血漿、痰、脳脊髄液または細胞もしくは組織ホモジネートなどの単離されたin vitro生物媒体とともにインキュベートした後に、またはin vivoにおいて対象を候補iRNA剤と接触させた後に候補iRNA剤の分解により形成される最も豊富なフラグメントの単離および同定、それによる切断を受けやすい部位の同定を含む。このような方法は例えば、限定されるものではないが、2005年5月27日出願の国際特許出願公報WO2005115481の中にある。
α−ENaC遺伝子発現を阻害し得ることが確認されたiRNA剤を動物モデル(例えば、マウス、ラット、モルモットまたは霊長類などの哺乳類)でin vivo機能性に関して試験することができる。例えば、iRNA剤を動物に投与し、そのiRNA剤をその生体分布、安定性およびそのα−ENaC発現阻害能またはα−ENaCにより少なくとも部分的に媒介される生物プロセスまたは病理プロセスを調節する能力に関して評価することができる。
本明細書では、単離されたiRNA剤、例えば、α−ENaC遺伝子の発現を阻害するためのRNAiを媒介するds RNA剤を記載する。
iRNA剤、例えば、α−ENaCを標的とするiRNA剤は、増強されたヌクレアーゼ耐性を有し得る。
iRNA剤の特性(その薬理学的特性を含む)は、例えば、リガンド、例えばテザードリガンドの導入により影響を与え、調整することができる。さらに、iRNA剤の薬理学的特性は、iRNA剤の薬理学的特性は、iRNA剤がテザードリガンドを有するか、テザードリガンドをまさに有する(does have)かのいずれかの場合にiRNA剤の製剤にリガンドを組み込むことによって改善することができる。
好ましい態様において、iRNA剤は5'リン酸化されているか、または5'プライム末端にホスホリル類似体を含む。アンチセンス鎖の5'−リン酸修飾は、RISC媒介遺伝子サイレンシングに適合するものを含む。好適な修飾としては、5'−一リン酸((HO)2(O)P−O−5');5'−二リン酸((HO)2(O)P−O−P(HO)(O)−O−5');5'−三リン酸((HO)2(O)P−O−(HO)(O)P−O−P(HO)(O)−O−5');5'−グアノシンキャップ(7−メチル化または非メチル化)(7m−G−O−5'−(HO)(O)P−O−(HO)(O)P−O−P(HO)(O)−O−5');5'−アデノシンキャップ(Appp)、および任意の修飾または非修飾ヌクレオチドキャップ構造(N−O−5'−(HO)(O)P−O−(HO)(O)P−O−P(HO)(O)−O−5');5'−一チオリン酸(ホスホロチオエート;(HO)2(S)P−O−5');5'−一ジチオリン酸(ホスホロジチオエート;(HO)(HS)(S)P−O−5')、5'−ホスホロチオレート((HO)2(O)P−S−5');酸素/硫黄置換一リン酸、二リン酸および三リン酸の任意のさらなる組合せ(例えば、5'−α−チオ三リン酸、5'−γ−チオ三リン酸など)、5'−ホスホルアミデート((HO)2(O)P−NH−5'、(HO)(NH2)(O)P−O−5')、5'−アルキルホスホネート(R=アルキル=メチル、エチル、イソプロピル、プロピルなど、例えば、RP(OH)(O)−O−5'−、(OH)2(O)P−5'−CH2−)、5'−アルキルエーテルホスホネート(R=アルキルエーテル=メトキシメチル(MeOCH2−)、エトキシメチルなど、例えば、RP(OH)(O)−O−5'−)が含まれる。
ニトロピロリルおよびニトロインドリルは、ユニバーサル塩基として知られる化合物種のメンバーである非天然核酸塩基である。ユニバーサル塩基は、オリゴヌクレオチド二本鎖の融解挙動または活性に実質的に影響を及ぼさずに4つの天然塩基のいずれかを置換することができる化合物である。天然核酸塩基に関連する安定化、水素結合相互作用とは対照的に、3−ニトロピロリル核酸塩基を含むオリゴヌクレオチド二本鎖が積層相互作用によって安定化されているに過ぎないと仮定される。ニトロピロリル核酸塩基との有意な水素結合相互作用が存在しないことで、特異的相補塩基に対する特異性が回避される。さらに、種々の報告から、4−、5−および6−ニトロインドリルが4つの天然塩基に対して極めて小さな特異性しか示さないことが確認される。興味深いことに、5−ニトロインドリルを含むオリゴヌクレオチド二本鎖は、4−ニトロインドリルおよび6−ニトロインドリルを含む対応するオリゴヌクレオチドよりも安定であった。1−(2'−O−メチル−β−D−リボフラノシル)−5−ニトロインドールの製造手順はGaubert, G.; Wengel, J. Tetrahedron Letters 2004, 45, 5629に記載されている。本発明に従う他のユニバーサル塩基としては、ヒポキサンチニル、イソイノシニル、2−アザ−イノシニル、7−デアザ−イノシニル、ニトロイミダゾリル、ニトロピラゾリル、ニトロベンズイミダゾリル、ニトロインダゾリル、アミノインドリル、ピロロピリミジニルおよびその構造的誘導体が挙げられる。合成手順を含め、ニトロピロリル、ニトロインドリルおよび上述のその他のユニバーサル塩基のより詳細な考察については、Vallone et al., Nucleic Acids Research, 27(17):3589-3596 (1999); Loakes et al., J. Mol. Bio., 270:426-436 (1997); Loakes et al., Nucleic Acids Research, 22(20):4039-4043 (1994); Oliver et al., Organic Letters, Vol. 3(13):1977-1980 (2001); Amosova et al., Nucleic Acids Research, 25(10):1930-1934 (1997); Loakes et al., Nucleic Acids Research, 29(12):2437-2447 (2001); Bergstrom et al., J. Am. Chem. Soc., 117:1201-1209 (1995); Franchetti et al., Biorg. Med. Chem. Lett. 11:67-69 (2001);およびNair et al., Nucelosides, Nucleotides & Nucleic Acids, 20(4-7):735-738 (2001)を参照。
特定の理論に縛られるものではないが、コレステロールコンジュゲートiRNA剤とリポタンパク質の特定の構成要素(例えば、コレステロール、コレステロールエステル、リン脂質)の化学的類似性は、iRNA剤と血中のリポタンパク質(例えば、LDL、HDL)との会合および/またはiRNA剤と、コレステロールに対する親和性を有する細胞成分、例えば、コレステロール輸送経路の成分との相互作用をもたらし得る。リポタンパク質ならびにそれらの構成要素は細胞により、種々の能動的および受動的輸送機構、例えば、限定されるものではないが、LDL受容体結合LDLのエンドサイトーシス、スカベンジャー受容体Aとの相互作用を介した酸化またはそれ以外の修飾を受けたLDLエンドサイトーシス、肝臓におけるスカベンジャー受容体B1により媒介されるHDLコレステロールの取り込み、飲細胞作用またはABC(ATP結合カセット)輸送体タンパク質、例えば、ABC−A1、ABC−G1もしくはABC−G4による膜を介したコレステロール輸送によって処理される。従って、コレステロールコンジュゲートiRNA剤は、例えば肝臓細胞など、このような輸送機構を有する細胞によって助長される取り込みを享受し得る。本発明はそれ自体、iRNA剤を、例えば受容体などの特定の細胞表面成分を発現する細胞に標的化するための(このような成分(例えばコレステロール)の天然リガンドをiRNA剤にコンジュゲートさせるか、または化学部分(例えばコレステロール)を該成分(例えば、LDL、HDL)の天然リガンドと会合もしくは結合するiRNA剤にコンジュゲートさせることによる)根拠および一般法を提供する。
iRNA剤は、in vivoにおいて細胞で、例えば、細胞に送達された外因性DNA鋳型から産生させることができる。例えば、DNA鋳型はベクターに導入し、遺伝子治療ベクターとして使用することができる。遺伝子治療ベクターは、例えば、静注、局所投与(米国特許第5,328,470号)または定位注射(例えば、Chen et al. Proc. Natl. Acad. Sci. USA 91:3054-3057, 1994参照)により対象に送達することができる。遺伝子治療ベクター医薬製剤は許容される希釈液中の遺伝子治療ベクターを含むことができ、あるいは遺伝子送達ビヒクルが包埋された徐放性マトリックスを含むことができる。例えばDNA鋳型は、iRNA剤のトップストランドを含む転写物を産生するものとiRNA剤のボトムストランドを含む転写物を産生スルものの2つの転写ユニットを含み得る。これらの鋳型が転写されると、iRNA剤は産生され、遺伝子サイレンシングを媒介するsiRNA剤フラグメントへとプロセシングされる。
本発明はまた、本発明のdsRNA化合物を含む医薬組成物および製剤も含む。本発明の医薬組成物は、局所処置が望まれるか全身処置が望まれるか、および処置される領域によっていくつかの方法で投与することができる。投与は局所投与、肺投与(例えばネブライザーによるものを含む、例えば粉末またはエアゾールの吸入または吹送による)、気管内投与、鼻腔内投与、上皮および経皮投与、経口投与または非経腸投与であり得る。非経腸投与には、静脈内、動脈内、皮下、腹腔内もしくは筋肉内注射もしくは注入;または頭蓋内、例えば、くも膜下腔内または脳室内投与が含まれる。
本発明の組成物はエマルションとして製造および調剤することができる。エマルションは一般に、一方の液体が他方の液体中に、通常は0.1μm径を超える液滴の形態で分散している不均一系である(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)。エマルションは多くの場合、緊密に混合し、互いに分散した2つの不混和液体相を含む二相系である。一般に、エマルションは、油中水(w/o)または水中油(o/w)型のいずれかであり得る。水相が多量の油性相中に微粉となり、微細な液滴として分散している場合には、得られる組成物は油中水(w/o)エマルションと呼ばれる。あるいは、油相が多量の水相中に微粉となり、微細な液体として分散している場合には、得られる組成物は水中油(o/w)エマルションと呼ばれる。エマルションは、分散相の他、付加的成分および薬剤(水相もしくは油相中の溶液として、またはそれ自体別個の相として提供することができる)を含んでもよい。必要に応じて、乳化剤、安定剤、色素および抗酸化剤などの医薬賦形剤がエマルション中に存在してもよい。医薬エマルションはまた、例えば、油中水中油(o/w/o)および水中油中水(w/o/w)エマルションなどの2相を超える相からなる多重エマルションであってもよい。このような複合体製剤は多くの場合、単純な二相エマルションが提供できない特定の利点を提供する。o/wエマルションの個々の油滴が小さな水滴を封入している多重エマルションはw/o/wエマルションをなす。同様に、油性の連続相中で安定化された水の小球に封入された油滴の系は、o/w/oエマルションとなる。
研究され、薬剤の調剤に用いられているマイクロエマルションの他にも多くの組織化された界面活性剤構造がある。これらには、単層、ミセル、二層および小胞が含まれる。リポソームなどの小胞は、薬剤送達の観点からそれらが与える特異性および作用期間のために多大な関心が寄せられている。本発明において「リポソーム」とは、球状二層または二層に配置された両親媒性脂質からなる小胞を意味する。
一態様では、本発明は、核酸、特に、dsRNAの、動物の皮膚への効率的な送達を果たすために種々の浸透促進剤を用いる。ほとんどの薬剤はイオン化形態と非イオン化形態の双方で溶液中に存在する。しかしながら、通常、脂質可溶性または親油性の薬剤だけが細胞膜を容易に通過する。非親油性薬剤であっても、通過させる膜を浸透促進剤で処置すると、細胞膜を通過し得ることが発見された。非親油性薬剤の細胞膜を経た拡散を補助する他、浸透促進剤はまた親油性薬剤の浸透性も高める。
本発明のある特定の組成物はまた、製剤に担体化合物も含む。本明細書において「担体化合物」または「担体」とは、不活性である(すなわち、それ自体生物活性を持たない)が、生物活性を有する核酸のバイオアベイラビリティを、例えば、生物学的に活性な核酸を分解するか、または循環からのその除去を促進することで低下させるin vivoプロセスによって核酸と認識される核酸、またはその類似体を指し得る。核酸と担体化合物を、一般には後者の物質を過剰にして同時投与すると、おそらくは担体化合物と核酸間の共通の受容体をめぐる競合のために、肝臓、腎臓またはその他の循環外貯蔵庫に回収される核酸量の実質的減少がもたらされ得る。例えば、肝臓組織における部分的ホスホロチオエートdsRNAの回収は、それがポリイノシン酸、デキストラン硫酸、ポリシチジン酸または4−アセトアミド−4'イソチオシアノ−スチルベン−2,2'−ジスルホン酸と同時投与される場合には減少され得る(Miyao et al., Antisense Res. Dev., 1995, 5, 115-121; Takakura et al., Antisense & Nucl. Acid Drug Dev., 1996, 6, 177-183)。
担体化合物とは対照的に、「医薬担体」または「賦形剤」は、1以上の核酸を動物に送達するための薬学上許容される溶媒、沈殿防止剤または他の任意の薬理学的に不活性なビヒクルである。賦形剤は液体または固体であってよく、計画された投与様式を念頭に置いて、所定の医薬組成物の核酸およびその他の成分と組み合わせた際に、所望の嵩、粘稠度などをもたらすように選択される。典型的な医薬としては、限定されるものではないが、結合剤(例えば、アルファー化トウモロコシデンプン、ポリビニルピロリドンまた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、ラクトースおよびその他の糖、微晶質セルロース、ペクチン、ゼラチン、硫酸カルシウム、エチルセルロース、ポリアクリレートまたはリン酸水素ナトリウムなど);滑沢剤(例えば、ステアリン酸マグネシウム、タルク、シリカ、コロイド二酸化ケイ素、ステアリン酸、金属ステアリン酸塩、硬化植物油、コーンスターチ、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、デンプン、グリコール酸ナトリウムデンプンなど);および湿潤剤(例えば、ラウリル硫酸ナトリウムなど)が挙げられる。
本発明の別の局面は、特に、嚢胞性繊維症の処置のための、iRNA剤の気道送達を提供する。気道には、中咽頭および喉頭を含む上気道と、それに続く、気管とそれに続く気管支および細気管支への分岐を含む下気道が含まれる。上下気道は導管気道と呼ばれる。その後、気管支末端は呼吸細気管支に分岐し、これは次に最終の呼吸器系領域である肺胞または肺深部に至る。導管気道の上皮は、α−ENaC iRNA剤などのiRNA剤の送達のための吸入用治療エアゾールの主な標的である。
本発明の組成物は、医薬組成物に通常見られるその他の補助成分を、それらの分野で確立された使用レベルでさらに含んでもよい。よって、例えば、これらの組成物は、例えば、鎮痒薬、収斂薬、局所麻酔または抗炎症薬などの付加的な、適合性の、薬学的に活性な物質を含んでもよく、または色素、香味剤、保存剤、抗酸化剤、不透明化剤、増粘剤および安定剤など、本発明の組成物の種々の投与形を物理的に調剤するのに有用な付加的物質を含んでもよい。しかしながら、このような物質は、付加した場合、本発明の組成物の成分の生物活性を過度に妨げてはならない。これらの製剤は安定化させることができ、所望により、例えば、滑沢剤、保存剤、安定剤、湿潤剤、乳化剤、浸透圧に影響を与えるための塩、バッファー、着色剤、香味剤および/または芳香族物質など、その製剤の核酸と有害な相互作用をしない補助剤と混合することができる。
iRNA剤、例えば、α−ENaCを標的とするiRNA剤を含む組成物は、作用部位への局所送達または対象への全身送達のいずれかを達成するための種々の経路によって、対象に送達することができる。経路の例としては、肺および鼻道などの治療部位への直接的局所投与、ならびに静脈内、鼻腔、経口および眼への送達が挙げられる。本発明のiRNA剤を投与する好ましい手段は、液体、エアゾールまたは霧状溶液としての、肺および鼻道への直接投与によるものである。
iRNA剤は、約75mg/kg体重未満、約70、60、50、40、30、20、10、5、2、1、0.5、0.1、0.05、0.01、0.005、0.001もしくは0.0005mg/kg体重未満、または200nmol未満のiRNA剤(例えば、約4.4×1016コピー)/kg体重、または1500、750、300、150、75、15、7.5、1.5、0.75、0.15、0.075、0.015、0.0075、0.0015、0.00075、0.00015nmol未満のiRNA剤/kg体重の単位用量で投与することができる。この単位用量は例えば、注射(例えば、静脈内または筋肉内、くも膜下腔内または臓器へ直接)、吸入投与または局所適用により投与することができる。
本明細書において試薬の供給源が特に示されていない場合には、そのような試薬は分子生物学用試薬のいずれかの供給者から、分子生物学における適用に標準的な品質/純度でから得ることができる。
上皮ナトリウムチャネルENaC(α−ENaC)のαサブユニットの発現をダウンレギュレーションするための治療用siRNAを同定するために、バイオインフォマティクス分析に基づいてスクリーニングセットを定義した。スクリーニングセットの設計のキードライバーは、関連のある種のトランスクリプトームに対するsiRNAの、推定される特異性であった。α−ENaC siRNAおよび効率的な送達系の同定のため、三部構成のアプローチを用いた:気管内送達後のin vivoサイレンシングの有効性に取り組むための試験種としてラットを選択し、α−ENaC mRNAの減少が測定可能な機能的効果をもたらすことを証明するための疾病モデル生物としてモルモットを選択した。治療用siRNA分子は、ヒトα−ENaCならびに少なくとも1種類の毒性学関連種、この場合にはアカゲザルのα−ENaC配列を標的としなければならない。
治療用スクリーニングセットは、ヒトおよびアカゲザルα−ENaC配列と完全に相補的なsiRNA配列だけを含むように設計した。
siRNAの設計は、これまでに定義されている4つのセットに対してsiRNAを同定するように行った(上記参照)。
a)「初期スクリーニングセット」
b)「拡張スクリーニングセット」
c)「ラットに関するin vivoサロゲートセット」
d)「モルモットに関するin vivoサロゲートセット」
初期スクリーニングセットのin silico選択の目的は、ヒトα−ENaCならびにそのアカゲザル相同分子種を特的に標的とするsiRNAを同定することである。ヒト標的mRNA(NM_001038.4)は、全siRNA選択手順の中で、NCBIリソース(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=nucleotide)からダウンロードした。α−ENaCアカゲザル(Macaca mulatta)相同分子種を同定するため、このヒト配列を2004年10月01日現在のMmulattaコンティグに対するBaylor College of Medicine(http://www.hgsc.bcm.tmc.edu/blast/?organism=Mmulatta)におけるblastn検索で用いた。全てのヒット領域を抽出し、CAPアセンブリツールによってアセンブルし、最初のアセンブリ配列を作成した。さらに、アカゲザルフリーズ(2005年3月12日)に対するUCSC(http://genome.ucsc.edu/cgi-bin/hgBlat?command=start&org=Rhesus&db=rheMac2&hgsid=84859356)においてヒト配列を用いたBLAST検索を行った。スキャフォールドヒット84554をダウンロードし、CAPにより、最初のアセンブリ配列とともに用いてアカゲザルα−ENaCの最終的なコンセンサス配列を作成した。
1)鎖の標的外能は、標的外に対するミスマッチの数および分布から推測することができる。
2)最も関連のある標的外、すなわち、ミスマッチの耐性のためにサイレンシングされる確率が最も高いと推定される遺伝子は、鎖の標的外能を決定する。
3)鎖の2〜9番の位置(5'から3'方向に数える)(シード領域)は、残りの配列(すなわち、非シード領域および切断部位領域)よりも標的外能により大きく寄与し得る(Haley, B., and Zamore, P.D., Nat Struct Mol Biol. 2004, 11:599)。
4)鎖の10番と11番の位置(5'から3'方向に数える)(切断部位領域)は、非シード領域(すなわち、5'から3'方向に数えて12〜18番の位置)よりも標的外能により大きく寄与し得る。
5)各鎖の1番と19番の位置は標的外能に関連がない。
6)標的外能は、仮説3〜5を考慮して、標的外遺伝子の最も相同な領域に対する鎖のミスマッチの数および位置に基づいて計算された、最も関連のある標的外の標的外スコアによって表すことができる。
7)導入された内部修飾によるセンス鎖活性化の中断の可能性を仮定すると、アンチセンス鎖の標的外能だけが関連する。
仮説3〜5の全ての可能性のある標的外をランク付けし、これにより最も関連のある標的外遺伝子およびその標的外スコアを特定するために、fastA出力ファイルをパールスクリプトにより分析した。
・非シード領域のミスマッチの数
・シード領域のミスマッチの数
・切断部位領域のミスマッチの数
標的外スコアは仮説3〜5を考慮して以下のように計算した。
標的外スコア=シードミスマッチの数*10
+切断部位ミスマッチの数*1.2
+非シードミスマッチの数*1
計算された標的外能をソーティングパラメーター(標的外スコアの降順)として用い、全てのヒト−アカゲザル交差反応性siRNA配列のランク付けを作成した。
拡張スクリーニングセットのin silico選択の目的は、アカゲザルとの交差反応性が無いために最初のセットから排除された、十分な特異性を有するヒトα−ENaCを標的とするさらなるsiRNAを全て同定することであった。分析されていなかったヒトα−ENaCに由来する19マーのプールからの残りの配列を取得し、対応するアンチセンス配列を作成した。最も関連のある標的外遺伝子およびその対応する標的外スコアを「初期スクリーニングセット」の節に記載されているように計算した。
in vivoラットサロゲートセットのin silico選択の目的は、ラットにおいて十分な特異性を有するヒトおよびラットα−ENaCを標的とする全てのsiRNAを同定することであった。ヒト−ラット交差反応性siRNAの同定のため、ラットα−ENaC mRNA配列をNCBIヌクレオチドデータベース(受託番号NM_031548.2)からダウンロードし、ヒト19マーのプールからの全ての配列を、ヒト−ラット交差反応性siRNA(センス)配列を表す配列ラット配列における存在に関して調べた。
in vivoモルモットサロゲートセットのin silico選択の目的は、それまでのセットで選択されていないヒトおよびモルモットα−ENaCを標的とする全てのsiRNAを同定することであった。それまでに判定されたヒト−モルモット交差反応性siRNA(センス)配列の残りのsiRNAを、ヒト標的外スコアに従ってランク付けした。in vivoモルモットサロゲートセットを表す、上の63配列(ポリG配列を除く)を選択した(表1d参照)。
天然塩基を含むヌクレオチドの合成
スクリーニングセットからのsiRNAが全てin vivo投与に意図される可能性があるので、siRNAを、生体環境中でのエンドおよびエキソヌクレアーゼによる分解からsiRNAを保護する改変戦略で合成した。この戦略では、両鎖の3'末端を、3'末端の最後の2つの核酸塩基の間のホスホロチオエート結合により、3'→5'エキソヌクレアーゼ活性から保護する。siRNAのエンドヌクレアーゼ分解を阻害するため、siRNAのセンス鎖の全てのピリミジンを対応する2'−O−メチル修飾リボヌクレオチドで置換した。より活性の高い、従って修飾に対する感受性の高い鎖であるアンチセンス鎖における修飾の数を減らすために、本発明者らはこれまでに同定されている主要なヌクレアーゼ切断部位に関してピリミジンのみを2'−O−メチル基で修飾した。この主要な切断部位は次の2つの配列モチーフ:5'−UA−3'および5'−CA−3'である。
本発明において試薬の供給源が特に示されない場合、そのような試薬は、分子生物学用試薬の供給者から分子生物学における適用に標準的な品質/純度で入手可能である。
iRNA剤のα−ENaC発現阻害能を、in vitroではヒト細胞系統で、またはin vivoではラットで試験した。iRNA剤を、例えばトランスフェクションにより細胞にトランスフェクトし、一定時間、例えば24時間細胞に作用させ、α−ENaC mRNAのレベルを分岐DNA分析により測定した。あるいは、in vivoにおいてiRNA剤を気管内経路により投与し、α−ENaC mRNA発現の阻害を標的器官に対する分岐DNA分析により測定した。これらの直接的アッセイの補足として、本発明者らは、哺乳類宿主細胞により組換え発現されたα−ENaC mRNAに対するRNAi剤による標的遺伝子発現の阻害を試験した。
H441細胞はAmerican Type Culture Collection(ATCC-Number: HTB-174, LCG Promochem GmbH, Wesel, Germany)から入手し、5%CO2/95%空気雰囲気下、37℃、RPMI 1640、10%ウシ胎児血清、100uペニシリン/100μg/mLストレプトマイシン、2mM L−グルタミン、10nM Hepesおよび1mMピルビン酸ナトリウム(全てBiochrom AG, Berlin, Germanyから)中で増殖させた。
トランスフェクション1日前に、H441細胞(ATCC-Number: HTB-174, LCG Promochem GmbH, Wesel, Germany)において、100nMのデキサメタゾンを加えることでENaC−α発現を誘発した。トランスフェクション直前に、細胞を96ウェルプレート(Greiner Bio-One GmbH, Frickenhausen, Germany)上、培養培地75μL(RPMI 1640、10%ウシ胎児血清、100uペニシリン/100μg/mlストレプトマイシン、2mM L−グルタミン、10nM Hepesおよび1mMピルビン酸ナトリウム、全てBiochrom AG, Berlin, Germanyから)中、1.5×104細胞/ウェルで播種した。トランスフェクションは4反復で行った。各ウェル0.5μLのリポフェクタミン2000(Invitrogen GmbH, Karlsruhe, Germany)を12μLのOpti-MEM(Invitrogen)と混合し、室温で15分間インキュベートした。トランスフェクション容量100μLでsiRNA濃度が50nMである場合、1μLの5μM siRNAをウェル当たり11.5μLのOpti-MEMと混合し、リポフェクタミン2000−Opti-MEM混合物と合わせ、再び室温で15分間インキュベートした。siRNA−リポフェクタミン2000−複合体を細胞に完全に適用し(ウェル当たり各25μL)、細胞を加湿インキュベーター(Heraeus GmbH, Hanau)中、37℃、5%CO2で24時間インキュベートした。
ヒト気管支上皮細胞(ドナー参照4F1499)をトランスフェクション1日前に、24ウェルプレートに0.5mL培養培地中、1×105細胞/ウェルでプレーティングした。細胞はsiRNAトランスフェクション当日、集密度70%であった。
表2Cは、siRNA例に関する一次HBECにおけるα−ENaC発現を示す。
カニクイザルα−ENaC配列のクローニング
5'−UTRおよびCDSの増幅のためのプライマー配列(括弧内に示されているヌクレオチドはMacaca mulatta(アカゲザル)α−ENaC cDNA配列に相当する):
P745:5'-CTCCATGTTCTGCGGCCGCGGATAGAAG-3'(nt1427)(配列番号1674)
P733:5'-CCGGCCGGCGGGCGGGCT-3'(nt1)(配列番号1675)
P734:5'-CTCCCCAGCCCGGCCGCT-3'(nt17)(配列番号1676)
P735:5'-GGCCGCTGCACCTGTAGG-3'(nt28)(配列番号1677)
P737:5'-ATGGAGTACTGTGACTACAGG-3'(nt1422)(配列番号:1678)
P740:5'-TTGAGCATCTGCCTACTTG-3'(nt3113)(配列番号:1679)
P713:5'-5'-ATGGATGATGGTGGCTTTAACTTGCGG-3'(nt1182)(配列番号:1710)
P715:5'-5'-TCAGGGCCCCCCCAGAGG-3'(nt2108)(配列番号:1680)
COS−1細胞を24ウェルプレート上の各0.5mLの培養培地中に6×104細胞/ウェルで播種した。播種1日後に細胞をpXOONカニクイザルα−ENaC発現プラスミドと示されたsiRNAで同時トランスフェクトした。下記のように、X-treme遺伝子トランスフェクション試薬(Roche)を3.75μL/ウェルにて、全量720μL/ウェルOpti-MEM(Invitrogen)で用い、4ngのα−ENaC発現プラスミドおよび600ngの担体プラスミド(pNFAT-luc)を関連のsiRNA(終濃度45nM)で同時トランスフェクトした。
siRNAの、インターフェロン−α(IFNα)放出刺激能を評価するため、siRNAを新たに精製した末梢血単核細胞(PBMC)とともに24時間インキュベートした。siRNAは、そのままPBMCに加えるか、またはまず脂質トランスフェクション剤(GenePorter 2またはリポフェクタミン2000またはDOTAPトランスフェクション剤)と複合体を形成させ、次に、PBMCとともにインキュベートするかのいずれかとした。IFNα誘導の陽性対照として、非修飾対照配列DI_A_2216およびDI_A_5167を含めた。
5'-dGsdGsdGdGdGdAdCdGdAdTdCdGdTdCdGsdGsdGsdGsdGsdG-3'(配列番号:1707)
DI_A_5167は、コレステロールコンジュゲートsiRNAである。
5'-GUCAUCACACUGAAUACCAAU-s-chol-3'(配列番号:1709)
3'-CsAsCAGUAGUGUGACUUAUGGUUA-5'(配列番号:1708)
主要治療配列の選択は、IFNα誘導のレベルが陽性対照の15%未満であることに基づいた。
痰サンプルはAhmet Uluer医師(ボストン小児病院)により採取された。収集後、痰サンプルは抗生物質で処理し、UV照射して細菌含量を減らした。痰サンプルにおけるsiRNA安定性を判定するため、siRNAを、5μM濃度の痰30μL中、37℃で示された時間インキュベートした。プロテイナーゼKの添加により反応を終わらせ、サンプルを42℃でさらに20分間インキュベートした。ヌクレアーゼ分解耐性のL−ヌクレオチドからなる40マーのRNA分子(「Spiegelmer」)を加え、較正標準として用いた。サンプルを0.2μm膜で濾過して残渣を除去した。サンプルを、pH11.0で、溶出に過塩素酸ナトリウム勾配を用いる、DNAPac PA 200カラム(Dionex)での変性イオン交換HPLCにより分析した。siRNAおよび分解生成物を、各サンプルのピーク下面積の測定によって定量した。濃度は非インキュベートサンプルにおける濃度に対して標準化した。
主要候補の標的部位から既知の多型を排除するため、主要siRNA配列をNCBI一塩基多型(SNP)データベース(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=snp)に対して確認した。ヒトSCNN1A遺伝子における既知の10種のエキソン多型で、最も有効な10種の主要治療薬候補のいずれかの標的部位に存在することが示されたものはなかった。
各配列のアライメントの一覧を19マー領域にわたる相同性により選別した。標的外を、実施例1に記載されている基準に従い、ミスマッチの数および位置に基づいてスコアリングした。上位5つの標的外配列を各主要治療配列(ND8356、ND8357およびND8396)に関して同定した。標的配列および標的外配列をそれぞれデュアルルシフェラーゼリポーター系にクローニングした。各クローニングフラグメントは、標的配列の5'および3'の双方に、10ヌクレオチドのフランキング領域に加えて標的19ヌクレオチドを包含した。これらのフラグメントをSV40プロモーターの制御下、ウミシイタケ・ルシフェラーゼ配列の3'側の多重クローニング部位にクローニングした。標的配列および標的外配列の双方に対する各siRNAの活性を、ホタル・ルシフェラーゼ(HSV−TKプロモーターにより独立に制御される)に対する標的ウミシイタケ・ルシフェラーゼの相対的蛍光により決定した。まず、COS−7細胞においてsiRNA濃度50nMでトランスフェクションを行った。ルシフェラーゼの読み取りは、トランスフェクション24時間後に行った。この高濃度のsiRNAでは、この3つの主要siRNAのいずれについてもいずれの標的外配列に対しても30%を超えるノックダウンは見られなかった。標的配列に対する活性は、ウミシイタケ・ルシフェラーゼ活性における相対的低下がおよそ80%であることで示した。また、標的配列に対する各siRNAについてIC50曲線も作成し、上記で同定された標的外配列を対照とした。各主要siRNAに関して、このリポーターアッセイにおける標的IC50は、H441において内在標的に対して得られたIC50(実施例3.3)と同じ桁であり(10〜50pM)、ND8356、ND8357およびND8396に関して、標的配列に対する効力は、推定される標的外配列のいずれよりも少なくとも1000〜5000倍高かったことを示す。
細胞傷害性の判定:細胞傷害性は、培養細胞数の評価のための細胞計数を用いることで判定した。
in vitroにおいて細胞傷害性濃度を試験することで、小核形成などの遺伝毒性作用が誘発され得ることがよく知られている。よって、本発明者らは、小核を有する細胞の非用量依存的な増加がせいぜい中程度の毒性を示す濃度ですでに認めることができれば、50%前後またはそれより低い(同時に行った陰性対照に比べて)細胞総数で小核を含む細胞の数の増加が見られることが細胞傷害性に関連すると考えた。in vitro哺乳類細胞アッセイを規制するガイドライン(染色体異常試験の実施に関するOECDおよびICHガイドライン)によれば、細胞総数に少なくとも50%の減少を示す濃度の分析が必要とされる。さらに、OECDプロトコールは、無毒な化合物を、少なくとも1種類の沈殿濃度を含むように(これが10mMまたは5mg/ml(いずれにせよ低い)を超えない限り)試験することを必要とする。in vitro小核試験は、調節アッセイ、すなわち、in vitro染色体異常試験の転帰を推定することを目的とするので、このin vitro小核試験のプロトコールはこれらの試験の要件を満たすように設計した。
・≧2%であり、同時に行った溶媒対照値の少なくとも2倍を示した場合、または
・<2%であり、同時に行った溶媒対照値の少なくとも3倍の増加を示した場合
に、試験濃度に関する小核誘導作用は陽性であるとみなした。
実験が陽性であると結論付けるためには、用量−作用関係と細胞傷害性を考慮しなければならない。
αENaCに対する主要siRNAのin vitro機能有効性を証明するため、H441細胞をsiRNAでトランスフェクトし、イオン輸送のUssingsチャンバー分析のために調製した。トランスフェクションのため、H441細胞をT25フラスコの、200nMデキサメタゾンを添加した培養培地中に、フラスコ当たり2×106細胞をプレーティングした。各フラスコの細胞をND8396または非標的対照siRNAのいずれかで、全量5mL(血清不含培地)中、30nM siRNAおよび4mL/mLリポフェクタミン2000にてトランスフェクトした。トランスフェクション1日後に、細胞を、分化および固着の形成に必要な時間を最短にするため、1cm2 Snapwellインサート上に集密状態(2×105細胞/インサート)でプレーティングし、上部と下部の双方に培地を供給した。さらに1日培養した後、上部の培地を除去し、下部の培地を交換し、このようにして細胞を空気−液体界面(ALI)培養とした。細胞をイオン輸送分析前さらに6日間ALIで維持した。
核酸配列を、標準的な命名法と、特に表Aの省略形を用い、以下に示す。
Claims (12)
- 以下からなる群から選択されるセンス鎖およびアンチセンス鎖を含む、iRNA剤:
配列番号1425および1426;
配列番号1431および1432;
配列番号1497および1498;
配列番号1297および1298;
配列番号1367および1368;
配列番号979および980;
配列番号223および224;
配列番号527および528;
配列番号1281および1282;
配列番号143および144;
配列番号189および190;
配列番号447および448;
配列番号493および494;
配列番号145および146;
配列番号57および58;
配列番号1511および1512;並びに、
配列番号1637および1638。 - ホスホロチオエートまたは2'−修飾ヌクレオチドを含む、請求項1に記載のiRNA剤。
- 少なくとも1つの5'−ウリジン−アデニン−3'(5'−ua−3')ジヌクレオチド(ここで、ウリジンは2'−修飾ヌクレオチドである);少なくとも1つの5'−ウリジン−グアニン−3'(5'−ug−3')ジヌクレオチド(ここで、5'−ウリジンは2'−修飾ヌクレオチドである);少なくとも1つの5'−シチジン−アデニン−3'(5'−ca−3')ジヌクレオチド(ここで、5'−シチジンは2'−修飾ヌクレオチドである);または少なくとも1つの5'−ウリジン−ウリジン−3'(5'−uu−3')ジヌクレオチド(ここで、5'−ウリジンは2'−修飾ヌクレオチドである)を含む、請求項1または2に記載のiRNA剤。
- 前記2'−修飾が、2'−デオキシ、2'−デオキシ−2'−フルオロ、2'−O−メチル、2'−O−メトキシエチル(2'−O−MOE)、2'−O−アミノプロピル(2'−O−AP)、2'−O−ジメチルアミノエチル(2'−O−DMAOE)、2'−O−ジメチルアミノプロピル(2'−O−DMAP)、2'−O−ジメチルアミノエチルオキシエチル(2'−O−DMAEOE)および2'−O−N−メチルアセトアミド(2'−O−NMA)からなる群から選択される、請求項1〜3のいずれか一項に記載のiRNA剤。
- 1以上の診断用化合物、リポーター基、架橋剤、ヌクレアーゼ耐性付与部分、天然または非通常核酸塩基、親油性分子、コレステロール、脂質、レクチン、ステロイド、ウバオール、ヘシゲニン、ジゴスゲニン、テルペン、トリテルペン、サルササポゲニン、フリーデリン、エピフリーデラノール誘導化リトコール酸、ビタミン、炭水化物、デキストラン、プルラン、キチン、キトサン、合成ポリマー、オリゴラクテート15マー、天然ポリマー、低分子量または中分子量ポリマー、イヌリン、シクロデキストリン、ヒアルロン酸、タンパク質、タンパク質結合剤、インテグリン標的分子、ポリカチオン、ペプチド、ポリアミン、ペプチドミミックス、および/またはトランスフェリンと結合されている、請求項1〜4のいずれか一項に記載のiRNA剤。
- a)請求項1〜5のいずれか一項に記載のiRNA剤と、
b)薬学上許容される担体
を含む、医薬組成物。 - 葉酸およびトランスフェリンから選択される上皮受容体リガンドを含む、請求項6に記載の医薬組成物。
- 嚢胞性繊維症、原発性腺毛ジスキネジア、慢性気管支炎、慢性閉塞性肺疾患(COPD)、喘息、気道感染、肺癌、リドル症候群、腎不全、高血圧症、または電解質平衡異常を治療および/または予防するための、請求項6または7に記載の医薬組成物。
- 嚢胞性繊維症を治療および/または予防するための、請求項8に記載の医薬組成物。
- リドル症候群を治療および/または予防するための、請求項8に記載の医薬組成物。
- 高血圧症および/または腎不全を治療および/または予防するための、請求項8に記載の医薬組成物。
- 電解質平衡異常を治療および/または予防するための、請求項8に記載の医薬組成物。
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