JP2021072843A - アポリポタンパク質c−iii(apoc3)の発現を阻害するための組成物及び方法 - Google Patents
アポリポタンパク質c−iii(apoc3)の発現を阻害するための組成物及び方法 Download PDFInfo
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Abstract
Description
本願は、その全体が参照により本明細書に組み込まれる、2011年6月23日出願の米国特許仮出願第61/499,620号明細書による利益を主張する。
本願は、201X年年月XXに作製されたX00,000バイトのサイズの11111US_sequencelisting.txtと命名されたテキストファイルとして電子的に提出された配列リストを含む。配列リストは、参照により組み込まれる。
利便性のために、明細書、実施例及び添付の特許請求の範囲に使用される所定の用語及びフレーズの意味を、以下に提供する。本明細書の他の部分における用語の使用と、このセクションに提供されるその定義との間に明らかな矛盾が存在する場合、このセクションの定義が優先するものとする。
本明細書により詳細に記載するように、本発明は、細胞又は哺乳動物内でAPOC3遺伝子の発現を阻害するための二重鎖リボ核酸(dsRNA)分子を提供し、dsRNAは、APOC3遺伝子の発現において形成されるmRNAの少なくとも一部に対して相補的な相補性の領域を有するアンチセンス鎖を含み、また相補性の領域が、30ヌクレオチド長未満であり、一般に19〜24ヌクレオチド長であり、また前記dsRNAが、前記APOC3遺伝子を発現する細胞と接触した後、例えばPCR若しくは分岐DNA(bDNA)ベースの方法、又はウェスタンブロットなどのタンパク質ベースの方法でアッセイして、前記APOC3遺伝子の発現を少なくとも30%阻害する。APOC3遺伝子の発現は、下記の実施例に記載したアッセイにより測定した際、少なくとも30%低下し得る。例えば、例えばHep3B細胞など細胞培養物内でのAPOC3遺伝子の発現は、例えばbDNA若しくはTaqManアッセイによりAPOC3 mRNAレベルを測定することにより、又は例えばELISAアッセイによりタンパク質レベルを測定することにより、アッセイすることができる。本発明のdsRNAは、更に1つ又は複数の一本鎖ヌクレオチドオーバーハングを含んでもよい。
更なる別の実施形態では、dsRNAを化学的に修飾して、安定性を向上させてもよい。本発明を特徴付ける核酸は、参照により本明細書に組み込まれる「Current protocols in nucleic acid chemistry,」Beaucage,S.L.et al.(Eds.),John Wiley&Sons,Inc.,New York,NY,USAに記載されているような、当技術分野にてよく確立された方法により合成及び/又は修飾することができる。本発明に有用なdsRNA化合物の特定の例は、修飾バックボーンを含む又は天然ヌクレオシド間結合を有さないRNAを含む。本明細書に定義されるように、修飾バックボーンを有するdsRNAは、バックボーン内にリン原子を保持するものと、バックボーン内にリン原子を有さないものとを含む。本明細書の目的において、及び、当技術分野にて時折言及されるように、それらのヌクレオシド間バックボーン内にリン原子を有さない修飾dsRNAも、オリゴヌクレオシドであると見なされてもよい。
本発明のdsRNAの他の修飾は、dsRNAの活性、細胞分布又は細胞取り込みを向上させる1つ又は複数の部分又はコンジュゲートをdsRNAに化学的に結合することを含む。そのような部分には、非限定的にコレステロール部分(Letsinger et al.,Proc.Natl.Acid.Sci.USA,1989,86:6553−6556)、コール酸(Manoharan et al.,Biorg.Med.Chem.Let.,1994,4:1053−1060)、チオエーテル、例えばベリル−S−トリチルチオール(Manoharan et al.,Ann.N.Y.Acad.Sci.,1992,660:306−309;Manoharan et al.,Biorg.Med.Chem.Let.,1993,3:2765−2770)、チオコレステロール(Oberhauser et al.,Nucl.Acids Res.,1992,20:533−538)、脂肪鎖、例えばドデカンジオール又はウンデシル残基(Saison−Behmoaras et al.,EMBO J,1991,10:1111−1118;Kabanov et al.,FEBS Lett.,1990,259:327−330;Svinarchuk et al.,Biochimie,1993,75:49−54)、リン脂質、例えばジ−ヘキサデシル−rac−グリセロール又はトリエチル−アンモニウム1,2−ジ−O−ヘキサデシル−rac−グリセロ−3−Hホスホネート(Manoharan et al.,Tetrahedron Lett.,1995,36:3651−3654;Shea et al.,Nucl.Acids Res.,1990,18:3777−3783)、ポリアミン又はポリエチレングリコール鎖(Manoharan et al.,Nucleosides&Nucleotides,1995,14:969−973)、又はアダマンタン酢酸(Manoharan et al.,Tetrahedron Lett.,1995,36:3651−3654)、パルミチル部分(Mishra et al.,Biochim.Biophys.Acta,1995,1264:229〜237)、又はオクタデシルアミン若しくはヘキシルアミノ−カルボニルオキシコレステロール部分(Crooke et al.,J.Pharmacol.Exp.Ther.,1996,277:923−937)などの脂質部分が挙げられる。
本発明の組成物及び方法のいくつかの実施形態では、dsRNAオリゴヌクレオチドは更に炭水化物を含む。炭水化物コンジュゲートdsRNAは、本明細書に記載するように、インビボでの核酸の送達に有利であり、また組成物は、インビボでの治療的使用に好適である。本明細書で使用される「炭水化物」は、少なくとも6個の炭素原子(直鎖状、分枝状又は環状であってもよい)を有し、該炭素原子の各々に酸素、窒素又は硫黄原子が結合している1つ又は複数の単糖単位から構成されている炭水化物それ自体である化合物;又はその一部として、1つ又は複数の単糖単位から構成されている炭水化物部分を有し、該単糖単位の各々が少なくとも6個の炭素原子(直鎖状、分枝状又は環状であってもよい)を有し、該炭素原子の各々に酸素、窒素又は硫黄原子が結合している化合物のいずれかを指す。代表的な炭水化物には、糖(単糖、二糖、三糖、及び、約4、5、6、7、8、又は9単糖単位を含むオリゴ糖)、並びに澱粉、グリコーゲン、セルロース及び多糖ゴムなどの多糖が挙げられる。特定の単糖には、C5以上(例えば、C5、C6、C7、又はC8)の糖が挙げられ;二及び三糖には、2つ又は3つの単糖単位(例えば、C5、C6、C7又はC8)を有する糖が挙げられる。
いくつかの実施形態において、本明細書に記載したコンジュゲート又はリガンドは、切断可能又は非切断可能であってもよい様々なリンカーを用いて、本発明のdsRNAに結合されてもよい。
P2A、P2B、P3A、P3B、P4A、P4B、P5A、P5B、P5C、T2A、T2B、T3A、T3B、T4A、T4B、T4A、T5B、T5Cは、各々、各存在に関して独立して不在、CO、NH、O、S、OC(O)、NHC(O)、CH2、CH2NH又はCH2Oであり;
Q2A、Q2B、Q3A、Q3B、Q4A、Q4B、Q5A、Q5B、Q5Cは、各存在に関して独立して不在、アルキレン、置換されたアルキレンであり、ここで1つ又は複数のメチレンは、O、S、S(O)、SO2、N(RN)、C(R’)=C(R’’)、C≡C又はC(O)のうちの1つ又は複数により中断又は終結されてもよく;
R2A、R2B、R3A、R3B、R4A、R4B、R5A、R5B、R5Cは、各々、各存在に関して独立して不在、NH、O、S、CH2、C(O)O、C(O)NH、NHCH(Ra)C(O)、−C(O)−CH(Ra)−NH−、CO、CH=N−O、
L2A、L2B、L3A、L3B、L4A、L4B、L5A、L5B及びL5Cは、リガンドを表し;即ち、各々、各存在に関して独立して単糖(GalNAcなどの)、二糖、三糖、四糖、オリゴ糖、又は多糖であり;Raは、H又はアミノ酸側鎖である。式(XXXV)のものなどの、三価コンジュゲートGalNAc誘導体は、RNAi剤と共に使用されて、標的遺伝子の発現を阻害するのに特に有用である:
式中、L5A、L5B及びL5Cは、GalNAc誘導体などの単糖を表す。
別の態様において、APOC3 dsRNA分子は、DNA又はRNAベクター内に挿入された転写単位から発現される(例えばCouture,A,et al.,TIG.(1996),12:5−10;Skillern,A.,et al.,国際PCT公開第00/22113号パンフレット、Conrad,国際PCT公開第00/22114号パンフレット、及びConrad,米国特許第6,054,299号明細書参照)。これらの導入遺伝子は、直鎖状コンストラクト、円形プラスミド、又はウィルスベクターとして導入されてもよく、これらは、宿主ゲノムに統合された導入遺伝子として組み込まれ及び遺伝され得る。導入遺伝子はまた、染色体外プラスミドとして遺伝されることが可能であるよう構成され得る(Gassmann et al.,Proc.Natl.Acad.Sci.USA(1995)92:1292)。
一実施形態において、本発明は、本明細書に記載したdsRNAと、薬学的に許容され得る担体とを含有する医薬組成物を提供する。dsRNAを含有する医薬組成物は、APOC3発現により媒介される病理過程などの、APOC3遺伝子の発現又は活性に関連した疾病又は疾患の処置に有用である。そのような医薬組成物は、送達モードに基づいて処方される。
本発明は、本発明を特徴付けるdsRNA化合物を含有する医薬組成物及び製剤も含む。本発明の医薬組成物は、局部又は全身処置のどちらが所望されるか、及び、処置されるべき範囲に応じて、多数の方法で投与され得る。投与は、局所(頬内及び舌下を含む)、経肺、例えば噴霧器を含む、粉末又はエアロゾルの吸入又は吹送により;気管内、鼻腔内、上皮及び経皮、経口又は非経口であってもよい。非経口投与には、静脈内、動脈内、皮下、腹腔内若しくは筋内注射若しくは注入;又は頭蓋内、例えば実質内、くも膜下腔内若しくは脳室内投与が挙げられる。
マイクロエマルションの他に、試験され、かつ薬物の製剤に使用されている多数の構築された界面活性剤構造が存在する。それらには、単層、ミセル、二重層及びベシクルが挙げられる。リポソームなどのベシクルは、それらが薬物送達の観点から提供する、それらの作用の特異性及び遅延に起因して多大な興味を引いてきた。本発明で使用される用語「リポソーム」は、球状の二重層に配置された両親媒性脂質から構成されるベシクルを意味する。
一実施形態において、本発明を特徴付けるAPOC3 dsRNAは、脂質製剤中に完全に封入されて、例えばSPLP、pSPLP、SNALP、又は他の核酸−脂質粒子を形成する。本明細書で使用される用語「SNALP」は、SPLPを含む安定な核酸−脂質粒子を指す。本明細書で使用される用語「SPLP」は、脂質ベシクル内に封入されたプラスミドDNAを含む核酸−脂質粒子を指す。SNALP及びSPLPは、典型的には、陽イオン性脂質、非陽イオン性脂質、及び粒子の凝集を防止する脂質(例えば、PEG−脂質コンジュゲート)を含む。SNALP及びSPLPは、静脈内(i.v.)注射後に延長された循環寿命を有し、かつ遠位部位(例えば、投与部位から物理的に分離された部位)に蓄積するため、全身適用に極めて有用である。SPLPは「pSPLP」を含み、pSPLPは、PCT公開第国際公開第00/03683号パンフレットに示されているように、封入された縮合剤−核酸複合体を含む。本発明の粒子は、典型的には、約50nm〜約150nm、より典型的には約60nm〜約130nm、より典型的には約70nm〜約110nm、最も典型的には約70nm〜約90nmの平均粒径を有し、かつ実質的に無毒である。加えて、核酸は、本発明の核酸−脂質粒子中に存在する場合、水性溶液中で、ヌクレアーゼによる分解に耐性である。核酸−脂質粒子、及びそれらの調製方法は、例えば米国特許第5,976,567号明細書;米国特許第5,981,501号明細書;米国特許第6,534,484号明細書;米国特許第6,586,410号明細書;米国特許第6,815,432号明細書;及びPCT公開国際公開第96/40964号パンフレットに開示されている。
本発明の組成物は、エマルションとして調製及び処方されてもよい。エマルションは、典型的には1つの液体が通常直径0.1μmを超える小滴の形態で他の液体に分散された不均一系である(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、互いに親密に混合され及び分散された2つの非混和性液体相を含む二層系である。一般に、エマルションは、油中水(w/o)又は水中油(o/w)の種類のいずれかであり得る。水性相が微小液滴として塊の油相中に微細に分割され及び分散された場合、得られた組成物は、油中水(w/o)エマルションと呼ばれる。代替的に、油相が微小液滴として塊の水性相中に微細に分割され及び分散された場合、得られた組成物は、水中油(o/w)エマルションと呼ばれる。エマルションは、分散相及び活性薬物に加えて追加の構成成分を含んでもよく、該構成成分は、水性相、油相中の溶液として、又はそれ自体が別個の相として存在してもよい。必要に応じてエマルション中に乳化剤、安定剤、染料、及び抗酸化剤などの医薬賦形剤も存在し得る。医薬エマルションは、例えば、油中水中油(o/w/o)及び水中油中水(w/o/w)エマルションの場合など、3つ以上の相からなる多エマルションであってもよい。そのような複合製剤は、多くの場合、単純な二成分エマルションが提供しない所定の利点を提供する。o/wエマルションの個々の油小滴が小さい水小滴を囲い込むする多エマルションは、w/o/wエマルションを構成する。同様に、油の連続相中で安定化された水の小球中に囲い込まれた油小滴の系は、o/w/oエマルションを提供する。
一実施形態において、本発明は、様々な浸透促進剤を使用して、核酸、特にdsRNAの動物の皮膚への効率的な送達を達成する。殆どの薬物は、溶液中でイオン化及び非イオン化形態の両方にある。しかしながら、通常、脂溶性又は親油性薬物のみが、細胞膜を容易に交差する。交差される細胞膜が透過促進剤で処理された場合、非親油性薬物さえも該膜を交差し得ることが発見されている。加えて、細胞膜を横切る非親油性薬物の分散を補助するために、浸透促進剤は親油性薬物の浸透性も向上させる。
本発明の所定の組成物は、製剤中に担体化合物も組み込んでいる。本明細書で使用される「担体化合物」又は「担体」は、不活性(即ち、生物学的活性perseを所有しない)であり得るが、例えば、生物学的に活性な核酸を分解し、又は循環からの核酸の除去を促進することによる、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下させるインビボでのプロセスによって、核酸であると認識される核酸又はその類似体を指すことができる。核酸及び担体化合物の共投与、典型的には過剰な後者の物質による共投与により、おそらくは共通の受容体に対する担体化合物と核酸との競合に起因して、肝臓、腎臓又は他の循環外リザーバ(extracirculatory reservoir)中で回収される核酸の量が実質的に低下し得る。例えば、肝組織内での部分的ホスホロチオエートの回収は、それがポリイノシン酸、デキストラン硫酸塩、ポリシチジル酸(polycytidic acid)又は4−アセトアミド−4’イソチオシアノ−スチルベン−2,2’−ジスルホン酸と共投与された際、低下され得る(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」又は「賦形剤」は、動物に1つ又は複数の核酸を送達するための薬学的に許容され得る溶媒、懸濁剤、又は任意の他の薬理学的に不活性なビヒクルである。賦形剤は、液体又は固体であってもよく、計画された投与方法を考慮に入れて、核酸及び医薬組成物の他の所定の構成成分と組み合わされた際に、所望の嵩、稠度などを提供するように選択される。典型的な医薬担体には、非限定的に、結合剤(例えば、α化トウモロコシ澱粉、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);充填剤(例えば、乳糖及び他の糖、微結晶セルロース、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、コロイド状二酸化ケイ素、ステアリン酸、金属ステアリン酸塩、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);錠剤崩壊剤(例えば、澱粉、澱粉グリコール酸ナトリウムなど);及び湿潤剤(例えば、ラウリル硫酸ナトリウムなど)が挙げられる。
本発明の組成物は更に、医薬組成物中に従来見出される他の補助構成成分も、当技術分野にて確立されたそれらの使用レベルで含有し得る。それ故、例えば、組成物は、例えば、鎮痒薬、収斂薬、局所麻酔薬若しくは抗炎症薬剤などの更なる、適合可能な、医薬的に活性な材料を含有してもよく、又は、染料、風味剤、保存剤、抗酸化剤、乳白剤、増粘剤及び安定剤などの、本発明の組成物の様々な剤形を物理的に処方するのに有用な更なる材料を含有してもよい。しかしながら、それらの材料は、加えられた際、本発明の組成物の構成成分の生物学的活性を過度に妨害しない必要がある。製剤は滅菌されてもよく、また所望の場合、製剤の核酸と有害に相互作用しない補助剤、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塩、緩衝液、着色料、調味料及び/又は芳香性物質などと混合される。
本発明はまた、本発明のdsRNA、及び/又は本発明のiRNAを含有する組成物を使用して、細胞内でのAPOC3発現を低減及び/又は阻害する方法も提供する。本方法は、細胞を本発明のdsRNAと接触させることと、細胞を十分な時間維持してAPOC3遺伝子のmRNA転写産物の分解を得ることによって、細胞内でのAPOC3遺伝子の発現を阻害することと、を含む。遺伝子発現の低下は、当技術分野にて既知の任意の方法により評価することができる。例えば、APOC3の発現の低下は、当業者に日常的な方法、例えばノーザンブロッティング、qRT−PCRを用いてAPOC3のmRNA発現レベルを決定することにより、ウェスタンブロッティング、免疫学的技術などの当業者に日常的な方法を用いてAPOC3のタンパク質レベルを決定することにより、並びに/又は、トリグリセリドレベルに関連した1つ又は複数の分子、例えばリポタンパク質リパーゼ(LPL)及び/若しくは肝性リパーゼに影響を与えることなどの、APOC3の生物学的活性を測定することにより、又はインビ環境内でトリグリセリドレベル自体を測定することにより決定することができる。
試薬供給源
本明細書に試薬供給源が特に与えられていない場合、それらの試薬は、分子生物学における任意の供給業者から、分子生物学での用途の品質/純度基準で得ることができる。
Expedite 8909合成機(Applied Biosystems,Applera Deutschland GmbH,Darmstadt,Germany)及び固相担体として多孔質ガラス(controlled pore glass)(CPG,500Å,Proligo Biochemie GmbH,Hamburg,Germany)を使用した固相合成により、一本鎖RNAを、1μmモルのスケールで生成した。RNAと、2’−O−メチルヌクレオチドを含むRNAとを、各々、対応するホスホロアミダイト及び2’−O−メチルホスホロアミダイトを使用して、固相合成により生成した(Proligo Biochemie GmbH,Hamburg,Germany)。これらの基本単位を、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的なヌクレオシドホスホロアミダイト化学を用い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結合は、ヨウ素酸化剤溶液をアセトニトリル中のBeaucage試薬(Chruachem Ltd,Glasgow,UK)の溶液(1%)で置き換えることにより導入した。更なる補助試薬は、Mallinckrodt Baker(Griesheim,Germany)から得た。
転写産物
siRNA設計を行って、NCBI遺伝子データベース(http://www.ncbi.nlm.nih.gov/gene/)に注釈が付けられている全てのヒト及びカニクイザル(Macaca fascicularis;以下「cyno」)APOC3転写産物を標的とするsiRNAを同定した。設計は、NCBIからの下記の転写産物を使用した:ヒト−NM_000040.1;cyno−X68359.1。リストされているヒト及びcyno転写産物と100%同一性を共有する全siRNA二本鎖を設計した。
siRNAを、予測される特異性、予測される効力、及びGC含有量に基づいて選択した。
合計で27のセンス及び27のアンチセンスに由来するsiRNAオリゴを合成し、二本鎖に形成した。
修飾及び非修飾ApoC3配列の合成
APOC3タイル配列を1又は0.2umolスケールのいずれかにてMerMade192合成機上で合成した。
APOC3配列(非修飾、2−O−メチル又は2’−フルオロ)の合成は、ホスホロアミダイト化学を使用した固相担体オリゴヌクレオチド合成を用いた。
APOC3タイル配列を沈殿させ、Sephadexカラムを使用してAKTA Purifierシステム上で精製した。このプロセスは、周囲温度で行った。サンプル注入及び収集は、96ウェル(深さ1.8mLのウェル)プレート内で行った。完全長配列に対応する単一ピークを、溶離液中に収集した。脱塩APOC3配列の濃度(A260でのUV測定により)及び純度(イオン交換HPLCにより)を分析した。次いで、相補的な一本鎖を1:1の化学量論比で組み合わせてsiRNA二本鎖を形成した。
細胞培養物及びトランスフェクション:
Hep3B細胞(ATCC,Manassas,VA)を5%CO2の雰囲気下、10%FBS、ストレプトマイシン及びグルタミン(ATCC)で補充したRPMI(ATCC)中、37℃でほぼコンフルエンスまで増殖させた後、トリプシン処理によりプレートから解放した。ウェル当たり14.8μlのOpti−MEM+0.2μlのLipofectamine RNAiMax(Invitrogen,Carlsbad CA.cat#13778−150を、96ウェルプレート内に、ウェル当たり5μlのsiRNA二本鎖に加えることによりトランスフェクションを行い、室温で15分間インキュベートした。次いで、抗生物質を有さない、〜2×104Hep3B細胞を含む80μlの完全増殖培地をsiRNA混合物に加えた。RNA精製に先だって細胞を24又は120時間のいずれかでインキュベートした。10nM及び0.1nMの最終二本鎖濃度で単一用量実験を行い、10、1、0.5、0.1、0.05、0.01、0.005、0.001、0.0005、0.0001、0.00005、0.00001nMの最終二本鎖濃度で用量応答実験を行った。
細胞を回収し、150μlの溶解/結合緩衝液中に溶解した後、エッペンドルフサーモミキサーを使用して、850rpmで5分間混合した(混合速度は、プロセス全体において同一であった)。10マイクロリットルの磁気粒及び80μlの溶解/結合緩衝液混合物を丸底プレートに加え、1分間混合した。磁気スタンドを使用して磁気粒を捕捉し、粒を乱すことなく上清を除去した。上清の除去後、溶解した細胞を残りの粒に加え、5分間混合した。上清の除去後、磁気粒を150μlの洗浄緩衝液Aで2回洗浄し、1分間混合した。粒を再度捕捉し、上清を除去した。次いで、粒を150μlの洗浄緩衝液Bで洗浄し、捕捉し、上清を除去した。次に粒を150μlの溶出緩衝液で洗浄し、捕捉し、上清を除去した。粒を2分間乾燥させた。乾燥後、50μlの溶出緩衝液を加え、70℃で5分間混合した。粒を磁石上で5分間捕捉した。40μlの上清を除去し、他の96ウェルプレートに加えた。
反応当たり2μlの10X緩衝液、0.8μlの25X dNTPs、2μlのランダムプライマー、1μlの逆転写酵素、1μlのRNAe阻害剤及び3.2μlのH2Oからなるマスターミックスを、10μlの総RNAに加えた。Bio−RadC−1000又はS−1000サーモサイクラー(Hercules,CA)を使用して、以下のステップを介してcDNAを生成した:25℃ 10分間、37℃ 120分間、85℃ 5秒間、4℃保持。
2μlのcDNAを、384ウェル50プレート(Roche cat#04887301001)内にて、ウェル当たり0.5μlのGAPDHTaqManプローブ(Applied Biosystems Cat#4326317E)、0.5μlのApoC3 TaqManプローブ(Applied Biosystems cat#Hs00163644_m1)及び5μlのLightcycler 480プローブマスターミックス(Roche Cat#04887301001)を含むマスターミックスに加えた。ΔΔCt(RQ)アッセイを用いて、ABI7900HT Real Time PCRシステム(Applied Biosystems)内でリアルタイムPCRを行った。概略表内に特に記さない限り、各二本鎖を2つの独立トランスフェクションにて試験し、各トランスフェクションを二回アッセイした。
HeLa及びHep3B細胞における細胞生存率を、100、10、1、0.1、0.01及び0.0001nMのsiRNAを用いたトランスフェクションから3、5日後に測定した。細胞を96ウェルプレート内でウェル当たり10,000細胞の密度で播種した。各siRNAを3回アッセイし、データを平均した。PLK1及びAD−19200を標的とするsiRNAを生存率の損失に関する正の対照として、AD−1955を負の対照として含めた。PLK1及びAD−19200は、生存率の用量依存性損失をもたらす。生存率を測定するために、3、5、日後に96ウェルプレートの各ウェルに20ulのCellTiter Blue(Promega)を加え、37℃で2時間インキュベートした。次いで、プレートを分光光度計(Molecular Devices)内にて560Ex/590Emで読み取った。生存率を3回の反復トランスフェクションからの光単位の平均値+/−標準偏差として表した。場合により、相対的な生存率は、最初に3回の反復トランスフェクションを平均した後、最低用量(0.001nM)から得られた値に対して正規化することにより評価した。
APOC3を標的とするsiRNAを、野生型(5.0mg/kg)及び遺伝子導入高脂血症モデルSREBPtg/LDLR−/−KOマウス(1.0mg/kg)の両方のマウスに投与した。投与から2日後にマウスを犠牲にし、肝標的mRNA、血清トリグリセリド、及び血清総コレステロールレベルを測定した。MC3を含むLNp11製剤を使用した。
追加の修飾APOC3 siRNAを、上述した方法を用いて、表6及び表7に記載したように合成した。UMdTdsdT修飾パターンは、dT−ホスホロチオエート−dTを各鎖に付加することである。DECAF修飾パターンは、以下の通りである:センス鎖−全ピリミジン上に2’O−メチル、dTsdT/dTdTオーバーハング;アンチセンス鎖−シード領域(2〜9位)内のジヌクレオチドモチーフUU/UA/UG内の任意の2つの部位における「U」を修飾+最終3ヌクレオチド(17〜19位)上に2’O−メチル+10〜16位の全部の「U」上に2’O−メチル;dTsdT/dTdTオーバーハング。FOME修飾パターンは、以下の通りである:センス鎖−2’F(5’第一の塩基)次いで2’OMeと交互、アンチセンス鎖−2’OMe(5’第一の塩基)、次いで2’Fと交互。
追加の修飾APOC3 siRNAを、上述した方法を用いて、表9及び表10に記載したように合成した。siRNAを、上述したようにHep3b細胞においてアッセイした。結果を表11に示す。
Claims (24)
- APOC3遺伝子の発現を阻害するための二重鎖リボ核酸(dsRNA)であって、前記dsRNAが、各々30ヌクレオチド長以下のセンス鎖及びアンチセンス鎖を含み、前記アンチセンス鎖が、表1、2、6、7又は10内のアンチセンス配列の少なくとも15連続ヌクレオチドを含む、二重鎖リボ核酸(dsRNA)。
- APOC3遺伝子の発現を阻害するための二重鎖リボ核酸(dsRNA)であって、前記dsRNAが、ヌクレオチド配列配列番号70からなるセンス鎖と、ヌクレオチド配列配列番号151からなるアンチセンス鎖とを含む、二重鎖リボ核酸(AD−45149.1UM)。
- 前記センス鎖配列が、表1、2、6、7又は10から選択され、前記アンチセンス鎖が、表1、2、6、7又は10から選択される、請求項1に記載のdsRNA。
- 前記dsRNAの少なくとも1つのヌクレオチドが、修飾ヌクレオチドである、請求項1又は2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を含むヌクレオチド、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結合された末端ヌクレオチドからなる群から選択される、請求項4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、固定ヌクレオチド、非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、及びヌクレオチドを含む非天然塩基からなる群から選択される、請求項4に記載のdsRNA。
- 少なくとも1つの鎖が、少なくとも1ヌクレオチドの3’オーバーハングを含む、請求項1〜6のいずれか一項に記載のdsRNA。
- 各鎖が、2ヌクレオチドに3’オーバーハングを含む、請求項1又は2に記載のdsRNA。
- 更にリガンドを含む、請求項1〜8のいずれか一項に記載のdsRNA。
- 前記リガンドが、前記dsRNAの前記センス鎖の3’末端にコンジュゲートされている、請求項9に記載のdsRNA。
- 更に少なくとも1つのN−アセチル−ガラクトサミンを含む、請求項1〜10のいずれか一項に記載のdsRNA。
- 請求項1〜11のいずれか一項に記載のdsRNAを含む細胞。
- 請求項1〜12のいずれか一項に記載のdsRNAの少なくとも1つの鎖をコードするベクター。
- 請求項13に記載のベクターを含む細胞。
- 請求項1〜14のいずれか一項に記載のdsRNAを含有する、APOC3遺伝子の発現を阻害するための医薬組成物。
- 脂質製剤を含有する、請求項15に記載の医薬組成物。
- MC3を含む脂質製剤を含有する、請求項15に記載の医薬組成物。
- 細胞内でのAPOC3発現の阻害方法であって:
(a)前記細胞を請求項1〜17のいずれか一項に記載のdsRNAと接触させることと;
(b)ステップ(a)で生成された前記細胞を十分な時間維持して、APOC3遺伝子のmRNA転写産物の分解を得ることによって、前記細胞内での前記APOC3遺伝子の発現を阻害することと、を含む、方法。 - 前記APOC3発現が少なくとも30%阻害される、請求項18に記載の方法。
- APOC3発現により媒介される疾患の処置方法であって、そのような処置を必要とするヒトに、治療的有効量の請求項1、2、若しくは11のいずれか一項に記載のAPOC3 dsRNA、又は請求項15〜17のいずれか一項に記載の医薬組成物を投与することを含む、方法。
- 前記疾患が高いトリグリセリドレベルである、請求項20に記載の方法。
- 前記疾患がトリグリセリドレベル>150mg/dL又は>500mg/dLである、請求項20に記載の方法。
- 投与がリポタンパク質リパーゼ及び/又は肝性リパーゼ活性の増大をもたらす、請求項20に記載の方法。
- 前記dsRNA又は前記医薬組成物が、約0.01mg/kg〜約10mg/kg又は約0.5mg/kg〜約50mg/kgの用量にて投与される、請求項20に記載の方法。
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