JP2013523650A - 眼への適用におけるrna干渉 - Google Patents
眼への適用におけるrna干渉 Download PDFInfo
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- JP2013523650A JP2013523650A JP2013501496A JP2013501496A JP2013523650A JP 2013523650 A JP2013523650 A JP 2013523650A JP 2013501496 A JP2013501496 A JP 2013501496A JP 2013501496 A JP2013501496 A JP 2013501496A JP 2013523650 A JP2013523650 A JP 2013523650A
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- rxrna
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- rxrnaori
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Abstract
Description
本願は、2010年3月24日に出願された米国仮出願第US 61/317,254号、表題「眼への適用におけるRNA干渉」および2010年3月25日に出願された米国仮出願第US 61/317,621号、表題「眼への適用におけるRNA干渉」の35 U.S.C. § 119(e)による利益を主張し、それらの出願の全開示は、その全体において本明細書において参考として組み込まれる。
本発明は、RNA干渉(RNAi)の分野に関する。本発明は、より具体的には、改善されたin vivo送達特性を有する核酸分子の眼への投与、および効率的な遺伝子サイレンシングにおけるそれらの使用に関する。
相補的なオリゴヌクレオチド配列は、有望な治療剤であって、遺伝子の機能を解明する上での有用な研究ツールである。しかし、先行技術のオリゴヌクレオチド分子は、その臨床的開発を妨げる可能性があるいくつかの問題に悩まされており、これは、かかる組成物を用いてのin vivoでの遺伝子発現(タンパク質合成を含む)の意図した効率的な阻害を達成することをしばしば困難にする。
ある側面において、上記の態様のいずれかのsd-rxRNAは、少なくとも1つの5−メチルCまたはU修飾を含む。
添付の図面は、原寸で描画されることを意図されていない。図面において、多様な図において示される各々の同一またはほぼ同一の成分は、類似の数詞により表わされる。明確化を目的として、全ての成分が全ての図面においてラベルされているわけではない。図面においては以下のとおりである。
本発明の側面は、遺伝子サイレンシングに関与する方法および組成物に関する。本発明は、少なくとも部分的に、sd-rxRNAの網膜下および硝子体内注射を含む眼への送達が、網膜色素上皮層を含む網膜中の全ての細胞層による効率的な分布および取り込みをもたらすという、驚くべき発見に基づく。sd-rxRNAに関して、従来のRNAi化合物に関するものよりも劇的により良好な網膜による取り込みおよび分布が観察される。したがって、sd-rxRNAは、眼の状態または障害の処置において多大な可能性を有する新たなクラスの治療用RNAi分子を表わす。
本発明の側面は、sd-rxRNA分子に関する。本明細書において用いられる場合、「sd-rxRNA」または「sd-rxRNA分子」とは、2009年9月22日に出願されたPCT公開番号WO2010/033247(出願番号PCT/US2009/005247)、表題「REDUCED SIZE SELF-DELIVERING RNAI COMPOUNDS」、において記載され、これから参考として組み込まれるもののなどの、自己送達性RNA分子に関する。簡単に述べると、sd-rxRNA(sd-rxRNAnanoとしてもまた言及される)は、単離された非対称二本鎖核酸分子であって、最短で16ヌクレオチドの長さを有するガイド鎖、および8〜18ヌクレオチドの長さのパッセンジャー鎖を含み、ここで、前記二本鎖核酸分子は、二本鎖領域と一本鎖領域とを有し、該一本鎖領域は、4〜12ヌクレオチドの長さを有し、少なくとも3ヌクレオチドの骨格修飾を有する。好ましい態様において、二本鎖核酸分子は、平滑であるかまたは1または2ヌクレオチドの突出を含む一方の末端を有する。sd-rxRNA分子は、化学修飾を通して、および一部の例においては疎水性の抱合体の結合を通して、最適化されていてもよい。
本発明のこの側面によれば、特定のガイド鎖修飾が、RNAi活性を著しく低下させることなく(またはRNAi活性を全く低下させることなく)、さらにヌクレアーゼ安定性を増大し、および/またはインターフェロン誘導を低下させる。
ある態様において、RNAiコンストラクトの構造は、ヒト、マウスおよび他のげっ歯類、ならびに他の非ヒト哺乳動物からの初代細胞を含む哺乳動物の初代細胞などの初代細胞において、インターフェロン応答を誘導しない。ある態様において、RNAiコンストラクトはまた、無脊椎生物において標的遺伝子の発現を阻害するために用いることができる。
哺乳動物は、さらに、対象となるRNAiコンストラクトと薬学的に受容可能なキャリアまたは希釈剤とを含む組成物に関する。
方法は、in vitroで、ex vivoで、またはin vivoで、例えば、培養中のヒト細胞などの培養中の哺乳動物細胞において行うことができる。
標的細胞(例えば哺乳動物細胞)は、脂質(例えばカチオン性脂質)またはリポソームなどの送達試薬の存在下において、接触させてもよい。
本発明の別の側面は、哺乳動物細胞において標的遺伝子の発現を阻害するための方法を提供し、該方法は、哺乳動物細胞を、対象となるRNAiコンストラクトを発現するベクターと接触させることを含む。
分子の他方の部分は、一本鎖領域である。一本鎖領域は、7〜40ヌクレオチドの範囲であると予測される。
より詳細な本発明の側面は、以下のセクションにおいて記載される。
本発明の二本鎖オリゴヌクレオチドは、2つの別々の相補的な核酸鎖により形成することができる。デュプレックス形成は、標的遺伝子を含有する細胞の内側で起きても外側で起きてもよい。
本発明のヌクレオチドは、糖部分、ホスホジエステル結合および/または塩基を含む、多様な位置において修飾することができる。
用語「ヒドロキシ」または「ヒドロキシル」は、−OHまたは−O-(適切な対イオンと共に)を有する基を含む。
用語「ハロゲン」は、フッ素、臭素、塩素、ヨウ素などを含む。用語「パーハロゲン化」は、一般に、全ての水素がハロゲン原子により置き換えられる部分を指す。
用語「ヌクレオチド」は、ホスファート基またはホスファートアナログをさらに含む、ヌクレオシドを含む。
Xは、NまたはCHであり;
Aは、結合;置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族であり;
R1は、疎水性部分であり;
R2は、水素;酸素保護基;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状の脂肪族;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状のヘテロ脂肪族;置換または未置換の、分枝鎖状または非分枝鎖状のアシル;置換または未置換の、分枝鎖状または非分枝鎖状のアリール;置換または未置換の、分枝鎖状または非分枝鎖状のヘテロアリールであり;および
R3は、核酸である。
ある態様において、Aは、結合である。ある態様において、Aは、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族である。ある態様において、Aは、非環式の、置換または未置換の、分枝鎖状または非分枝鎖状の脂肪族である。ある態様において、Aは、非環式の、置換された分枝鎖状または非分枝鎖状の脂肪族である。ある態様において、Aは、非環式の、置換された非分枝鎖状脂肪族である。ある態様において、Aは、非環式の、置換された非分枝鎖状アルキルである。ある態様において、Aは、非環式の、置換された非分枝鎖状C1〜20アルキルである。ある態様において、Aは、非環式の、置換された非分枝鎖状C1〜12アルキルである。ある態様において、Aは、非環式の、置換された非分枝鎖状C1〜10アルキルである。ある態様において、Aは、非環式の、置換された非分枝鎖状C1〜8アルキルである。ある態様において、Aは、非環式の、置換された非分枝鎖状C1〜6アルキルである。ある態様において、Aは、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族である。ある態様において、Aは、非環式の、置換または未置換の、分枝鎖状または非分枝鎖状のヘテロ脂肪族である。ある態様において、Aは、非環式の、置換された分枝鎖状または非分枝鎖状のヘテロ脂肪族である。ある態様において、Aは、非環式の、置換された非分枝鎖状ヘテロ脂肪族である。
Rの各々の出現は、独立して、天然または非天然のアミノ酸の側鎖であり;および
nは、1〜20の整数である(1および20を含む)。ある態様において、Aは、式:
式中、nは、1〜20の整数である(1および20を含む)。ある態様において、Aは、式:
式中、nは、1〜20の整数である(1および20を含む)。ある態様において、Aは、式:
式中、X、R1、R2およびR3は、本明細書において定義されるとおりであり;および
A’は、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族である。
式中、RAは、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族である。
Xは、NまたはCHであり;
Aは、結合;置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族であり;
R1は、疎水性部分であり;
R2は、水素;酸素保護基;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状の脂肪族;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状のヘテロ脂肪族;置換または未置換の、分枝鎖状または非分枝鎖状のアシル;置換または未置換の、分枝鎖状または非分枝鎖状のアリール;置換または未置換の、分枝鎖状または非分枝鎖状のヘテロアリールであり;および
R3は、核酸である。
Xは、NまたはCHであり;
Aは、結合;置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族であり;
R1は、疎水性部分であり;
R2は、水素;酸素保護基;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状の脂肪族;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状のヘテロ脂肪族;置換または未置換の、分枝鎖状または非分枝鎖状のアシル;置換または未置換の、分枝鎖状または非分枝鎖状のアリール;置換または未置換の、分枝鎖状または非分枝鎖状のヘテロアリールであり;および
R3は、核酸である。
Xは、NまたはCHであり;
Aは、結合;置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状の脂肪族;または、置換または未置換の、環式または非環式の、分枝鎖状または非分枝鎖状のヘテロ脂肪族であり;
R1は、疎水性部分であり;
R2は、水素;酸素保護基;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状の脂肪族;環式または非環式の、置換または未置換の、分枝鎖状または非分枝鎖状のヘテロ脂肪族;置換または未置換の、分枝鎖状または非分枝鎖状のアシル;置換または未置換の、分枝鎖状または非分枝鎖状のアリール;置換または未置換の、分枝鎖状または非分枝鎖状のヘテロアリールであり;および
R3は、核酸である。
nは、1〜20の整数である(1および20を含む)。
ある態様において、ガイド配列を超えるヌクレオチドの殆どまたは全ては(2’修飾されていようがいまいが)ホスホロチオエート結合により結合している。かかるコンストラクトは、その血清タンパク質に対するより高いアフィニティーに起因して、薬物動態学が改善されている傾向がある。ポリヌクレオチドの非ガイド配列部分におけるホスホロチオエート結合は、一般に、一旦ガイド鎖がRISCにロードされた後は、ガイド鎖の活性に干渉しない。
本発明のオリゴヌクレオチドは、当該分野において公知の任意の方法により、例えば、酵素による合成および/または化学合成を用いて、合成することができる。オリゴヌクレオチドは、in vitroで(例えば、酵素による合成および化学合成を用いて)、またはin vivoで(当該分野において周知の組み換えDNA技術を用いて)合成することができる。
細胞によるオリゴヌクレオチドの取り込み
オリゴヌクレオチドおよびオリゴヌクレオチド組成物は、1または2以上の細胞または細胞ライセートと接触させられ(すなわち、接触させられる、または本明細書においては投与または送達されるとして言及される)、これに取り込まれる。用語「細胞」は、原核および真核細胞、好ましくは脊椎動物細胞、およびより好ましくは哺乳動物細胞を含む。好ましい態様において、本発明のオリゴヌクレオチド組成物は、ヒト細胞と接触させられる。
送達されるRNA分子は、グルカン粒子と複合体形成するか、またはそのシェル(shell)の中に「捕捉(trap)」される。Soto and Ostroff (2008) Bioconjug Chem 19:840において記載され、これから参考として組み込まれるように、粒子のシェルまたはRNA成分を可視化のために標識することができる。GeRPをロードする方法は、以下にさらに議論される。
封入剤は、オリゴヌクレオチドを小胞中に封入(entrap)する。本発明の別の態様において、オリゴヌクレオチドは、キャリアまたはビヒクル、例えばリポソームまたはミセルと関連していてもよいが、当業者により理解されるであろうように、別のキャリアを用いることができる。リポソームは、生体膜に類似する構造を有する脂質二重層から作られるビヒクルである。オリゴヌクレオチドの細胞取り込みまたは標的化を促進するために、またはオリゴヌクレオチドの薬物動態学的もしくは毒物学的特性を改善するために、かかるキャリアを用いる。
本発明の目的のために、用語「ステロール型分子」は、ステロイドアルコール類を指し、これは、ステロールと構造が類似する。主要な差異は、環の構造、および21位に結合する側鎖の炭素の数である。
本発明の目的のために、用語「フィトステロール」(また、植物ステロールとも称される)は、植物において天然に存在する植物化学物質である、一群のステロイドアルコール類である。200種を超える既知のフィトステロールが存在する。
中性脂質混合物として、天然に存在する、または化学合成された、または修飾された、飽和および不飽和脂肪酸残基のクラスから選択される製剤が挙げられる。脂肪酸は、トリグリセリド、ジグリセリドまたは個々の脂肪酸の形態において存在し得る。別の態様において、薬理学において非経口栄養のために現在用いられている脂肪酸のよく確認された混合物および/または脂質乳液を利用してもよい。
複合体化剤は、強力であるが共有結合ではない引力(例えば、静電気、ファンデルワールス、パイ・スタッキングなどの相互作用)により、本発明のオリゴヌクレオチドに結合する。一態様において、本発明のオリゴヌクレオチドは、オリゴヌクレオチドの細胞による取り込みを増大するために、複合体化剤と複合体化してもよい。複合体化剤の一例として、カチオン性脂質が挙げられる。カチオン性脂質は、オリゴヌクレオチドを細胞へ送達するために用いることができる。しかし、上記のとおり、カチオン性脂質を含まない製剤が、一部の態様において好ましい。
オリゴヌクレオチドの送達はまた、オリゴヌクレオチドを細胞受容体へ標的化することによっても改善し得る。標的化部分は、オリゴヌクレオチドに抱合させても、オリゴヌクレオチドに結合したキャリア基(すなわち、ポリ(L−リジン)またはリポソーム)に結合させてもよい。この方法は、特異的受容体により媒介されるエンドサイトーシスを示す細胞に良好に適する。
オリゴヌクレオチドの最適な投与または送達の経路は、所望の結果および/または処置される対象に依存して変化し得る。本明細書において用いられる場合、「投与」は、細胞をオリゴヌクレオチドに接触させることを指し、in vitroで、またはin vivoで行うことができる。標的核酸分子から翻訳されるタンパク質の発現を最適に減少させるために、オリゴヌクレオチドの投与量を、例えばRNA安定性の読み出しによりまたは治療応答により測定されるものとして、過度の実験なしに調整することができる。
本明細書において記載される方法を通して投与されたsd-rxRNA分子は、眼内の全ての細胞型に対して効率的に標的化される。
一部の態様において、本発明のオリゴヌクレオチドは、安定であり、すなわち、エンドヌクレアーゼおよびエクソヌクレアーゼ分解に対して実質的に安定である。オリゴヌクレオチドは、それが内因性の細胞ヌクレアーゼによる攻撃に対して少なくとも約3倍耐性が高い場合に、ヌクレアーゼに対して実質的に耐性であるとして、および、それが対応するオリゴヌクレオチドよりも少なくとも約6倍耐性が高い場合に、高度にヌクレアーゼ耐性であるとして、定義される。これは、当該分野において公知である技術を用いて本発明のオリゴヌクレオチドがヌクレアーゼに対して実質的に耐性であることを示すことにより、実証することができる。
遺伝子の発現を阻害することにより、本発明のオリゴヌクレオチド組成物は、タンパク質の発現を伴う任意の疾患を処置するために用いることができる。オリゴヌクレオチド組成物により処置することができる疾患の例として、単に説明するために、癌、網膜症、自己免疫疾患、炎症性疾患(すなわち、ICAM-1関連障害、乾癬、潰瘍性大腸炎、クローン病)、ウイルス疾患(すなわち、HIV、C型肝炎)、miRNA障害、および心血管性疾患が挙げられる。
上で議論されるように、本明細書において記載される方法により投与されるsd-rxRNA分子は、眼内の全ての細胞型に対して、効率的に標的化される。
本発明の側面は、血管新生および/または血管漏出に関連する疾患および状態を処置することに関する。これらの状態のうち、滲出型AMDおよびDMEが、最も蔓延しており、PDRおよびRVOに続発する黄斑浮腫は蔓延性がより低く、稀な新生血管状態はROPおよび新生血管緑内障を含む。血管漏出はDMEの背後に存在する駆動力であると考えられ、一方、血管漏出と血管新生との両方がPDRを駆動する。本発明のオリゴヌクレオチド組成物は、特定の疾患または状態の病因に基づいて選択することができる。例えば、血管の浸透性に影響を及ぼす抗血管新生オリゴヌクレオチドを含む組成物を、DMEを処置するために選択することができ、一方、増殖に影響を及ぼすものを、PDRを処置するために選択することができる。あるいは、オリゴヌクレオチド組成物は、抗血管新生剤、例えば、血管の浸透性に影響を及ぼす標的の機能を阻害するsd-rxRNAと、増殖に影響を及ぼす標的の機能を阻害するsd-rxRNAとを、当該状態の両方の病因的側面が標的となるように含んでもよい。
一部の態様において、sd-rxRNAは、結合組織増殖因子(CTGF)、別名、肥大軟骨細胞特異的タンパク質24を標的とする。CTGFは、分泌型ヘパリン結合タンパク質であって、創傷治癒および強皮症に関連付けられてきた。結合組織増殖因子は、線維芽細胞、筋線維芽細胞、内皮および上皮細胞を含む多くの細胞型において活性である。ヒトCTGFについてのDNAおよびタンパク質の配列情報を提供する代表的なGenbankアクセッション番号は、NM_001901.2およびM92934である。
一部の態様において、sd-rxRNAは、TIE1(免疫グロブリン様およびEGF様ドメインを有するチロシンキナーゼ)を標的とする。
本発明の側面は、脈絡膜の血管新生を処置することに関し、これは、AMDの最も速い進行の形態であり(米国において約100万の症例)、脈絡膜から網膜下空間内への新たな血管の不適切な増殖およびこれらの血管からの体液の漏出から生じる。処置されない場合、患者の75%が3年以内に法的盲へと進行する。硝子体内における抗VEGF剤は、CNV病変の成長およびCNV病変からの血管漏出を阻害することにより、迅速に視力を改善することができる。しかし、存在する抗VEGF剤は、殆どの患者において既に存在する病変の退縮を引き起こすことはできない。
DMEは、網膜血管からの血管漏出から生じ、視力を脅かす網膜黄斑中の体液の蓄積をもたらし、糖尿病患者のうち約2〜5%において起こる。現在の治療の標準は、局所または格子状レーザー光凝固である。硝子体内における抗VEGF剤および副腎皮質ステロイドは、有効であることが示されているが、未だ承認されていない。
PDRは、慢性の網膜虚血に付随する。網膜の血管新生は、網膜虚血に続発的に起こり、硝子体出血、血管結合組織の増殖、および牽引性網膜剥離をもたらし得る。
ある態様において、sd-rxRNAは、PDRを処置するために用いられる。一部の態様において、sd-rxRNAは、VEGFを標的とする。他の態様において、sd-rxRNAは、HIF-1α、mTOR、PDGF-B、SDF-1、IGTA5、ANG2、CTGF、COX-2または補体因子3もしくは5を標的とする。一部の態様において、PDRの処置は、各sd-rxRNAが異なる遺伝子を標的とするsd-rxRNAの組み合わせの使用を含む。
RVOは、虚血性および非虚血性の形態で起こり得る。虚血性RVOは、黄斑浮腫、網膜虚血および血管新生を含む幾つかの視力を脅かす合併症をもたらし得る。非虚血性RVOは、より好ましい予後を有し、最も一般的な視力を脅かす合併症は、黄斑浮腫である。
ある態様において、the sd-rxRNAは、RVOに続発する黄斑浮腫を処置するために用いられる。一部の態様において、sd-rxRNAは、VEGFを標的とする。他の態様において、sd-rxRNAは、HIF-1α、mTOR、PDGF-B、SDF-1、IGTA5、ANG2、CTGF、COX-2または補体因子3もしくは5を標的とする。一部の態様において、RVOに続発する黄斑浮腫の処置は、各sd-rxRNAが異なる遺伝子を標的とするsd-rxRNAの組み合わせの使用を含む。
NVGは、重篤な慢性の眼の虚血を患う眼において発症する稀な障害である。最も一般的な原因は、進行性PDRまたは虚血性CRVOである。虹彩の血管新生は、虚血に起因して起こり、最終的に線維柱帯網を閉塞して重篤な続発性緑内障をもたらす。
ある態様において、sd-rxRNAは、虹彩の血管新生および/またはNVGを処置するために用いられる。一部の態様において、sd-rxRNAは、VEGFを標的とする。他の態様において、sd-rxRNAは、HIF-1α、mTOR、PDGF-B、SDF-1、IGTA5、ANG2、CTGF、COX-2または補体因子3もしくは5を標的とする。一部の態様において、虹彩の血管新生および/またはNVGの処置は、各sd-rxRNAが異なる遺伝子を標的とするsd-rxRNAの組み合わせの使用を含む。
増殖性網膜疾患として、増殖性硝子体網膜症、増殖性糖尿病性網膜症(PDR)、網膜上膜(網膜黄斑の表面の上に増殖し得る細胞の透明な層であり、網膜の牽引を引き起こす)および滲出型AMDが挙げられる。
ある態様において、sd-rxRNAは、増殖性網膜疾患を処置するために用いられる。一部の態様において、sd-rxRNAはTGFβを標的とし、一方、他の態様において、sd-rxRNAはCTGFを標的とする。なお他の態様において、複数のsd-rxRNAが、PDGFRα、mTOR、IGTA5、またはそれらの組み合わせを標的とする。さらに他の態様において、複数のsd-rxRNAが、TGFβと、CTGF、PDGFRα、mTOR、IGTA5、またはそれらの組み合わせの少なくとも1つとを標的とする。さらなる態様において、複数のsd-rxRNAが、CTGFと、TGFβ、PDGFRα、mTOR、IGTA5、またはそれらの組み合わせの少なくとも1つとを標的とする。ある態様において、増殖性網膜疾患の処置は、各sd-rxRNAが異なる遺伝子を標的とするsd-rxRNAの組み合わせの使用を含む。
ある態様において、sd-rxRNAは、地図状萎縮(GA)(滲出型AMDよりも遅く進行する萎縮型(dry)AMDの一形態)および初期〜中期型萎縮AMD(GAまたはCNVに先行する萎縮性AMDの初期段階)を含む萎縮型AMDを処置するために用いられる。、一部の態様において、sd-rxRNAは、Alu転写を標的とする。他の態様において、sd-rxRNAは、DICER(RNaseIIIファミリー中のエンドリボヌクレアーゼであって、二本鎖RNA(dsRNA)およびpre-microRNA(miRNA)を、低分子干渉RNA(siRNA)と称される約20〜25ヌクレオチド長の短い二本鎖RNAフラグメントへ切断するもの)の発現を阻害または調節する転写因子または他の分子を標的とする。
嚢胞様黄斑浮腫は、手術後の中心窩嚢胞(erofoveal cysts)における網膜内液の蓄積である。ある態様において、sd-rxRNAは、嚢胞様黄斑浮腫を処置するために用いられる。一部の態様において、sd-rxRNAは、COX-2(シクロオキシゲナーゼ−2)酵素を標的とする。
網膜色素変性症は、幾つかの既知の遺伝子における変異により引き起こされる遺伝性網膜変性疾患である。ある態様において、sd-rxRNAは、網膜色素変性症を処置するために用いられる。一部の態様において、sd-rxRNAは、NADPHオキシダーゼを標的とする。
緑内障は、視神経の変性により特徴づけられる、緩徐進行性疾患である。周辺部における初期の視力喪失と、疾患の進行したステージにおける中心部の視力の喪失とがある。緑内障関連視力喪失について最も理解されている危険因子は、眼内圧(IOP)である。線維柱帯切除術は、眼の前部からの過剰の体液を排出させ、IOPの低下をもたらすために、強膜を通してチャネルまたはブレブ(bleb)を作製するために設計された外科的手法である。線維柱帯切除術の失敗の最も一般的な原因は、瘢痕組織によるブレブの封鎖である。
ぶどう膜炎は、ぶどう膜と称される脈絡膜、毛様体および虹彩からなる眼の中間層の炎症により特徴づけられる広範な群の障害である。この障害は、解剖学的に、前部、中間部、後部または汎ぶどう膜炎として分類され、病理学的に、感染性または非感染性として分類される。
網膜芽細胞腫は、網膜の細胞中で急速に発達する癌である。ある態様において、sd-rxRNAは、網膜芽細胞腫を処置するために用いられる。一部の態様において、sd-rxRNAは、腫瘍性形質転換において役割を有すると考えられる核タンパク質であるHMGA2を標的とする。
例1:sd-rxRNA分子の眼投与
網膜下および硝子体内投与が、眼内の細胞型の全てにsd-rxRNA分子を送達する上で高度に有効であることを見出した。MAP4K4を標的とする、または非標的化sd-rxRNA(DY547標識を有するもの、または有しないもの)を、網膜下または硝子体内投与のいずれかにより注射した。5および10μgの用量を評価した。炎症の徴候は観察されなかった。眼は健常であるように見え、細胞遊走の徴候(炎症性応答の指標)は観察されなかった。
図4は、sd-rxRNAが網膜を光受容体の外節へ浸透することを明らかにする。
図5は、ARPE-19細胞において、sd-rxRNAが、rxRNAoriと比較して、強力な取り込みおよびサイレンシングを示すことを明らかにする。
図6は、眼の適応症における使用のためのsd-rxRNAの幾つかの非限定的な例を示す。
図8は、硝子体内投与の後でのsd-rxRNAの効率的な浸透を明らかにする。
蛍光標識されたRNAi化合物を、1μlの硝子体内注射を用いて、マウスの眼に投与した。注射の2〜3時間後までに、sd-rxRNAは神経節細胞層において存在し、投与の24時間後までに光受容体の外節において存在した。蛍光は、レーザー走査型共焦点顕微鏡を用いて検出した。
表3は、SPP1に対して向けられたsd-rxRNA分子の非限定的な例を表わす。
表4は、PTGS2(COX-2)に対して向けられたsd-rxRNAの配列の非限定的な例を表わす。
表5は、CTGFに対して向けられたsd-rxRNAの配列の非限定的な例を表わす。
表6は、TGFβ2に対して向けられたsd-rxRNAの配列の非限定的な例を表わす。
表7は、TGFβ1に対して向けられたsd-rxRNAの配列の非限定的な例を表わす。
sd-rxRNA開発のための最適な配列を、配列選択アルゴリズムを用いて同定した(表2)。当該アルゴリズムは、以下の基準に基づいて配列を選択する:32%より高いが47%より低いGC含有量、特定の動物モデル(例えば、マウスまたはラット)に対する相同性、5個以上のU/Uの伸長および/または2個以上のG/Cの伸長の回避、500未満のオフ・ターゲットヒットスコア、ならびに5’UTR中に含まれる配列の回避。
表9は、VEGFに対して向けられたrxRNAoriの配列の非限定的な例を表わす。
表10は、VEGFに対して向けられたsd-rxRNAの配列の、多様な化学修飾パターンを用いた最適化の結果を表わす。
図19は、リンカーの化学のバリエーションがin vitroでのsd-rxRNAのサイレンシング活性に影響を及ぼさないことを示す。ヒドロキシプロリンリンカーおよびリボリンカーの、2種の異なるリンカーの化学を、複数のsd-rxRNA(Map4k4またはPPIBを標的とする)について、受動的取り込みアッセイにおいて評価し、自己送達に有利なリンカーを決定した。HeLa細胞を、送達ビヒクルの不在下において(受動的トランスフェクション)、1uM、0.1uMまたは0.01uMでsd-rxRNAにより、48時間、トランスフェクトした。いずれのリンカーの使用も、sd-rxRNAの効果的な送達をもたらした。
当業者は、慣用的な実験のみを用いて、本明細書において記載される発明の具体的な態様への多数の均等物を理解するか、またはそれに気付くことができる。かかる均等物は、以下の特許請求の範囲により包含されることが意図される。
Claims (55)
- 核酸をそれを必要とする対象の眼に送達するための方法であって、
対象の眼に、sd-rxRNAを、眼における該sd-rxRNAによるRNA干渉を促進するための有効量において投与すること
を含む、前記方法。 - sd-rxRNAの投与が硝子体内である、請求項1に記載の方法。
- 眼の障害を処置するためのものである、請求項1または2に記載の方法。
- 眼の障害が、血管漏出、血管新生、加齢黄斑変性(AMD)、脈絡膜血管新生(滲出型AMD)、地図状萎縮(進行性萎縮型AMD)、初期〜中期型萎縮AMD、術後嚢胞様黄斑浮腫(CME)、非増殖性糖尿病性網膜症(NPDR)、糖尿病性黄斑浮腫(DME)、網膜静脈閉塞症(RVO)に続発する黄斑浮腫、増殖性糖尿病性網膜症(PDR)、緑内障、新生血管緑内障(NVG)、未熟児網膜症(ROP)、線維増殖性網膜疾患、増殖性硝子体網膜症(PVR)、網膜上膜/硝子体黄斑癒着、網膜変性疾患、網膜色素変性症、網膜血管閉塞性障害、網膜静脈閉塞症、網膜動脈閉塞症、網膜芽細胞腫、瘢痕形成に起因する線維柱帯切除術の失敗、およびぶどう膜炎からなる群より選択される、請求項3に記載の方法。
- 眼の障害が加齢黄斑変性(AMD)である、請求項4に記載の方法。
- 眼の障害が糖尿病性黄斑浮腫(DME)である、請求項4に記載の方法。
- 眼の障害が増殖性硝子体網膜症(PVR)である、請求項4に記載の方法。
- 眼の障害が、瘢痕形成に起因する線維柱帯切除術の失敗である、請求項4に記載の方法。
- sd-rxRNAが、VEGF、MAP4K4、PDGF-B、SDF-1、IGTA5、ANG2、CTGF、HIF-1α、mTOR、SDF-1、PDGF-B、SPP1、PTGS2(COX-2)、TGFβ1、TGFβ2、補体因子3および5、PDGFRa、PPIB、ならびにmyc、またはそれらの組み合わせからなる群より選択されるタンパク質をコードする遺伝子に対して向けられている、請求項1〜8のいずれか一項に記載の方法。
- sd-rxRNAがVEGFをコードする遺伝子に対して向けられている、請求項9に記載の方法。
- sd-rxRNAがCTGFをコードする遺伝子に対して向けられている、請求項9に記載の方法。
- 2または3以上の異なるタンパク質をコードする遺伝子に対して向けられている2または3以上の異なるsd-rxRNAが、両方とも対象の眼に投与される、請求項1〜11のいずれか一項に記載の方法。
- sd-rxRNAが、VEGFおよびCTGFに対して向けられているsd-rxRNAを含む、請求項12に記載の方法。
- sd-rxRNAが、VEGFおよびPTGS2(COX-2)に対して向けられているsd-rxRNAを含む、請求項12に記載の方法。
- sd-rxRNAが、表2中の配列から選択される配列に対して向けられている、請求項10に記載の方法。
- sd-rxRNAが、表2中の配列から選択される配列の少なくとも12の連続するヌクレオチドに対して向けられている、請求項10に記載の方法。
- sd-rxRNAが、表3〜8または10中の配列から選択される配列の少なくとも12の連続するヌクレオチドを含む、請求項1〜16のいずれか一項に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号1317または配列番号1357の配列の少なくとも12の連続するヌクレオチドを含む、請求項10に記載の方法。
- sd-rxRNAのアンチセンス鎖が、配列番号1318または配列番号1358の配列の少なくとも12の連続するヌクレオチドを含む、請求項10に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号1317を含み、sd-rxRNAのアンチセンス鎖が、配列番号1318を含む、請求項10に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号1357を含み、sd-rxRNAのアンチセンス鎖が、配列番号1358を含む、請求項10に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号1379を含み、sd-rxRNAのアンチセンス鎖が、配列番号1380を含む、請求項10に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号1397を含み、sd-rxRNAのアンチセンス鎖が、配列番号1398を含む、請求項10に記載の方法。
- sd-rxRNAのアンチセンス鎖が、配列番号948または配列番号964の配列の少なくとも12の連続するヌクレオチドを含む、請求項11に記載の方法。
- sd-rxRNAのセンス鎖が、配列番号947または配列番号963の配列の少なくとも12の連続するヌクレオチドを含む、請求項11に記載の方法。
- sd-rxRNAが疎水性に修飾されている、請求項1〜25のいずれか一項に記載の方法。
- sd-rxRNAが、1または2以上の疎水性の抱合体に結合している、請求項26に記載の方法。
- sd-rxRNAが、少なくとも1つの5−メチルCまたはU修飾を含む、請求項1〜27のいずれか一項に記載の方法。
- 核酸を、それを必要とする対象の眼に送達するための方法であって、
対象の眼に、rxRNAoriを、眼における該rxRNAoriによるRNA干渉を促進するための有効量において投与すること
を含む、前記方法。 - rxRNAoriが、VEGFに対して向けられている、請求項29に記載の方法。
- rxRNAoriが、表2中の配列から選択される配列の少なくとも12の連続するヌクレオチドを含む配列に対して向けられている、請求項30に記載の方法。
- rxRNAoriのセンス鎖が、配列番号13または配列番号28の配列の少なくとも12の連続するヌクレオチドを含む、請求項31に記載の方法。
- rxRNAoriのアンチセンス鎖が、配列番号1377または配列番号137828の配列の少なくとも12の連続するヌクレオチドを含む、請求項31に記載の方法。
- 表2中の配列から選択される配列に対して向けられている、sd-rxRNA。
- 表2中の配列から選択される配列の少なくとも12の連続するヌクレオチドを含む配列に対して向けられている、sd-rxRNA。
- 表3〜8または10中の配列から選択される配列の少なくとも12の連続するヌクレオチドを含む、sd-rxRNA。
- sd-rxRNAのセンス鎖が、配列番号1317、1357、1379または1397の配列の少なくとも12の連続するヌクレオチドを含む、請求項34〜36のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAのアンチセンス鎖が、配列番号1318、1358、1380または1398の配列の少なくとも12の連続するヌクレオチドを含む、請求項34〜37のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAのセンス鎖が、配列番号1317を含み、sd-rxRNAのアンチセンス鎖が、配列番号1318を含む、請求項34〜38のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAのセンス鎖が、配列番号1357を含み、sd-rxRNAのアンチセンス鎖が、配列番号1358を含む、請求項34〜38のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAのセンス鎖が、配列番号1379を含み、sd-rxRNAのアンチセンス鎖が、配列番号1380を含む、請求項34〜38のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAのセンス鎖が、配列番号1397を含み、sd-rxRNAのアンチセンス鎖が、配列番号1398を含む、請求項34〜38のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAが、疎水性に修飾されている、請求項34〜38のいずれか一項に記載のsd-rxRNA。
- sd-rxRNAが、1または2以上の疎水性の抱合体に結合している、請求項43に記載のsd-rxRNA。
- sd-rxRNAが、少なくとも1つの5−メチルCまたはU修飾を含む、請求項34〜44のいずれか一項に記載のsd-rxRNA。
- 請求項34〜45のいずれか一項に記載のsd-rxRNAを含む、組成物。
- VEGF以外のタンパク質をコードする遺伝子に対して向けられたsd-rxRNAをさらに含む、請求項46に記載の組成物。
- CTGFおよび/またはPTGS2(COX-2)をコードする遺伝子に対して向けられたsd-rxRNAを含む、請求項47に記載の組成物。
- 表2中の配列から選択される配列に対して向けられた、rxRNAori。
- 表2中の配列から選択される配列の少なくとも12の連続するヌクレオチドを含む配列に対して向けられた、rxRNAori。
- rxRNAoriのセンス鎖が、配列番号13または配列番号28の配列の少なくとも12の連続するヌクレオチドを含む、請求項49または50に記載のrxRNAori。
- rxRNAoriのアンチセンス鎖が、配列番号1377または配列番号1378の配列の少なくとも12の連続するヌクレオチドを含む、請求項49〜51のいずれか一項に記載のrxRNAori。
- 請求項49〜52のいずれか一項に記載のrxRNAoriを含む、組成物。
- VEGF以外のタンパク質をコードする遺伝子に対して向けられたrxRNAoriをさらに含む、請求項53に記載の組成物。
- CTGFおよび/またはPTGS2(COX-2)をコードする遺伝子に対して向けられたrxRNAoriを含む、請求項53に記載の組成物。
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JP6335968B2 (ja) | 2018-05-30 |
JP2020023498A (ja) | 2020-02-13 |
US10184124B2 (en) | 2019-01-22 |
US10662430B2 (en) | 2020-05-26 |
US20210062195A1 (en) | 2021-03-04 |
US9095504B2 (en) | 2015-08-04 |
JP2016193913A (ja) | 2016-11-17 |
US20130131142A1 (en) | 2013-05-23 |
CN103200945A (zh) | 2013-07-10 |
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CA2794187C (en) | 2020-07-14 |
JP2018150328A (ja) | 2018-09-27 |
JP5940054B2 (ja) | 2016-06-29 |
EP2550001A1 (en) | 2013-01-30 |
JP6815457B2 (ja) | 2021-01-20 |
CN103200945B (zh) | 2016-07-06 |
US11584933B2 (en) | 2023-02-21 |
CA2794187A1 (en) | 2011-09-29 |
WO2011119871A1 (en) | 2011-09-29 |
EP3578183A1 (en) | 2019-12-11 |
US20190233826A1 (en) | 2019-08-01 |
US20160115482A1 (en) | 2016-04-28 |
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