JP2009513617A - 眼疾患の治療のための、11β―ヒドロキシステロイド脱水素酵素の発現の調節 - Google Patents
眼疾患の治療のための、11β―ヒドロキシステロイド脱水素酵素の発現の調節 Download PDFInfo
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Abstract
Description
Bunce et al., 2005, Associations between the deletion polymorphism of the angiotensin 1-converting enzyme gene and ocular signs of primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol.; 243(4); 294 Costagliola et al., 2000, Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects. Exp Eye Res 71 (2): 167 Costagliola et al., 1995, . Effect of oral captopril (SQ 14225) on intraocular pressure in man. Eur J Ophthalmol., 5(1):19 Cullinane et al., 2002, Renin-angiotensin system expression and secretory function in cultured human ciliary body non-pigmented epithelium. Br J Ophthalmol., 86(6):676 Sakaguchi et al., 2002, Chymase and angiotensin converting enzyme activities in a hamster model of glaucoma filtering surgery. Curr Eye Res. 24(5):325 Shah et al., 2000, Oculohypotensive effect of angiotensin- converting enzyme inhibitors in acute and chronic models of glaucoma. J Cardiovasc Pharmacol., 36(2):169 Wang et al., 2005, Effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure in glaucomatous monkey eyes. Exp Eye Res., 80(5):629. Fire et al., 1998, Potent and specific genetic interference by double stranded RNA in Caenorhabditis elegans. Nature, 391:806 Bosher & Labouesse, 2000, RNA interference: genetic wand and genetic watchdog. Nat Cell Biol, 2000, 2(2):E31 Akashi et al., 2001 , Suppression of gene expression by RNA interference in cultured plant ceils. Antisense Nucleic Acid Drug Dev, 11 (6):359 Williams, 1997, Role of the double-stranded RNA-activated protein kinase (PKR) in cell regulation. Biochem Soc Trans, 25(2):509 Gil & Esteban, 2000, Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action. Apoptosis, 5(2):107-14 Wianny & Zernicka-Goetz, 2000, Specific interference with gene function by double-stranded RNA in early mouse development. Nat Cell Biol, 2(2):70 Eibashir et al., 2001 , RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev, 15(2):188 Caplen et al., 2001 , Specific inhibition of gene expression by small double stranded RNAs in invertebrate and vertebrate systems. Proc. Natl. Acad. Sci. USA, 98: 9742 Paddison et al, 2002, Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian ceils. Genes Dev, 16(8):948 Banerjee & Slack, Control of developmentai timing by small temporal RNAs: a paradigm for RNA-mediated regulation of gene expression. Bioessays, 2002, 24(2):119-29 Grosshans & Slack, 2002, Micro-RNAs: small is plentiful. J Cell Biol, 156(1):17 Davson H. The aqueous humour and intraocular pressure. In: Davson's Physiology of the Eye, 5th edn London, Macmillan Press, 1990:3-95 Hart WM. Intraocular pressure In: Hart WM, ed. Adler's Physiology of the Eye. St Louis, Mosby-Year Book Inc, 1992:248-267 Tomlinson JW. 11 Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target. Minerva Endocrinol. 2005 Mar;30(1):37-46 Rauz S, Walker EA, Shackleton CHL, Hewison M, Murray Pl, Stewart PM. Expression and putative role of 11β-hydroxysteroid dehydrogenase isozymes within the human eye. Invest Ophthalmol Vis Sci 2001 ; 42:2037-42 Suzuki T, Sasano H, Kaneko C, Ogawa S, Darnel AD, Krozowski ZS. lmmunohistochemical distribution of 11 β- hydroxysteroid dehydrogenase in human eye. MoI Cell Endocrinol 2001 ; 173:121-5 Mirshahi M, Nicolas C, Mirshahi A, Hecquet C, d'Hermies F, Faure JP, et al.The mineralocorticoid hormone receptor and action in the eye. Biochem Biophys Res Commun 1996; 219:150-6 Stokes J, Noble J, Brett L, Philips C, Seckl JR, O'Brien C, et al. Distribution of glucocorticoid and mineralocorticoid receptors and 11 β-hydroxysteroid dehydrogenases in human and rat ocular tissues. Invest Ophthalmol Vis Sci 2000; 41:1629-38 Rauz S, Cheung CM, Wood PJ, Coca-Prados M, Walker EA, Murray Pl, Stewart PM. Inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension. QJM, 2003 Jul;96(7):481-90
●センスとアンチセンスの一本鎖を常に別個の実験でテストする。
●スクランブルのsiRNA二本鎖を試す。これは、使用するsiRNAと同じヌクレオチドの組成物を持つが、(使用するsiRNAを含む)他のどの遺伝子とも、決定的な配列の相同性を欠いているべきである。
●可能であれば、2つの独立したsiRNA二本鎖を用いて同じ遺伝子をノックダウンし、抑制(silencing)プロセスの特異性を制御する。
好ましくは、RNAは化学的に合成され、それには、適切に保護されたリボヌクレオチドフォスフォアミダイト(phosphoramidite)及び従来どおりのDNA/RNA合成装置を用いる。siRNA2本鎖の、2’‐デオキシ、または2’‐O‐メチル、のオリゴリボヌクレオチドによる、片方または両方の鎖の置換は、ハエの抽出物(fly extract)(Elbashir et al. 2001)においては、抑制(silencing)を無効にする。しかし、哺乳類細胞では、センスsiRNAを、2’‐O‐メチルオリゴリボヌクレオチドによって置換することは可能であると思われる(Ge et al. RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription. Proc Natl Acad Sci U S A., 2003; 100(5):2718-23)。
●別々に等分して、50μMの濃度に各RNAオリゴを希釈する。
●各RNAオリゴ溶液30μlと5Xアニーリングバッファー15μlを混合する。バッファーの最終濃度は:100mM酢酸カリウム、30mM HEPES−KOH pH7.4、2mM 酢酸マグネシウム。最終量は75μlである。
●90℃で1分間、溶液をインキュベーションし、15秒間チューブを遠心し、37℃で1時間置いてから、室温で使用する。溶液は‐20℃で凍らせて保存が可能であり、5回までは凍結融解が可能である。siRNAの2本鎖の最終濃度は、通常20μMである。また、既にアニーリングされているdsRNAを供給業者から購入してもよい。
siRNA干渉の特異性を確かめるために、標的遺伝子を発現するさまざまな細胞培養がなされ、例えばそれは、無色素の毛様体上皮細胞(non−pigmented ciliary epithelium cell)であるNPE、毛様体上皮細胞であるOMDC、または胎児腎細胞であるHEK293を用いる。また、細胞膀胱癌の細胞株であるT−24、肺癌の細胞株であるA549、またはヒトの胎児性ケラチノサイト(human embryonic keratinocyte)であるHEKを使用する。
当該技術分野で周知の技術のいくつかの例は以下の通りである:我々は、陽イオン性脂質を用いるsiRNA2本鎖の単一のトランスフェクション(single transfection)を行い、陽イオン性脂質には例えば、RNAiFect Transfection Reagent(Qiagen)及びLipofectamine2000 Reagent(Invitrogen)があり、トランスフェクション後24、48及び72時間での抑制(silencing)について評価する。
標的タンパク質の、豊富さ及びライフタイム(life time)(つまり代謝回転)に依存して、ノックダウンの表現型は、1から3日後、またはそれ以降に明らかになる可能性がある。表現型がまったく観察されない場合には、タンパク質の枯渇が、免疫蛍光法及びウェスタンブロットによって観察される可能性がある。
ニュージーランドウサギは、IOPを研究するためにデザインされた、実験プラットフォームにおける最高の判断水準である。扱い易く、大きな眼を有しており、人間の器官とサイズが似ている。加えて、IOPを測定するための現在の装置は、眼の小さな動物(例えばマウスやラット)においての使用には適していない。最後に、ウサギは(約23mm Hgの)IOPを有し、局所性の商業的な降圧薬を使用して、その値を40%まで引き下げることが可能となる。したがって、ウサギの緑内障モデルを作り出すことが可能であるにも関わらず(例えば、外科的に強膜上静脈(episclerotic vein)を阻害しまたは人工的に小柱網を閉塞させる)、我々は、自分たちの管理下における、正常血圧のウサギを用いており、その理由は、IOPの薬理学的な減少が簡単に可能であり、再現性良く測定が可能だからである。
正常血圧のニュージーランド白ウサギ(雄、2‐3kg)を用いた。これらの動物を食事と水に、自由にありつける、別々のケージの中で飼育した。人工的に12時間の昼/夜サイクルで管理し、IOPの制御不能な日周振動を避け、並びに、動物の扱いと処置は、European Communities Council Directive(86/609/EEC)、the Association for Research in Visionの声明及びOphthalmology on the Use of Animals in Ophthalmic及びVision Researchにしたがって行った。
Claims (26)
- 眼疾患の治療のための医薬の製造におけるsiNAの使用であって、前記siNAが11β―ヒドロキシステロイド脱水素酵素1(11β―HSD1)の発現を阻害することができる使用。
- 前記眼疾患が、患者においての眼内圧(IOP)の変化を特徴とする、請求項1に記載の使用。
- 前記眼疾患が、緑内障、感染、炎症、ブドウ膜炎、及び全身性疾患の発現を含む群から選択される、請求項1または2に記載の使用。
- 前記眼疾患が緑内障である、請求項1から3のいずれか一項に記載の使用。
- 前記眼疾患が糖尿病性網膜症である、請求項1から4のいずれか一項に記載の使用。
- 標的遺伝子の発現が、前記患者の眼において阻害される、請求項1から5のいずれか一項に記載の使用。
- 前記siNAがsiRNAである、請求項1から6のいずれか一項に記載の使用。
- 前記siRNAがdsRNAである、請求項7に記載の使用。
- 前記siRNAがshRNAである、請求項7に記載の使用。
- 前記siNAが1つまたはそれより多い修飾オリゴヌクレオチドを含む、請求項1から9のいずれか一項に記載の使用。
- 前記siNAを患者の眼に局所的に投与する、請求項1から10のいずれか一項に記載の使用。
- 前記siNAを患者の角膜に投与する、請求項11に記載の使用。
- 複数の種類のsiNAを使用する、請求項1から12のいずれか一項に記載の使用。
- 前記複数の種類が同一種類のmRNAを標的とする、請求項13に記載の使用。
- 前記siNAが、配列番号1から61から選択される配列、または配列番号1から61を含む配列を標的とする、請求項1から14のいずれか一項に記載の使用。
- 前記標的遺伝子が11β−HSD1であり、前記siNAが、配列番号1から61から選択される配列、または配列番号1から61を含む配列を標的とする、請求項1から15のいずれか一項に記載の使用。
- 本発明のsiNA分子が配列番号62から122の群から選択されるヌクレオチド配列を含む、請求項1から16のいずれか一項に記載の使用。
- 前記siNA分子が3’オーバーハングを含む、請求項17に記載の使用。
- siNAを投与することを含む眼疾患の治療方法であって、前記siNAが11β−HSD1の発現を阻害することができる方法。
- 配列番号1から61から選択されるヌクレオチド配列に相補的な配列を含む、11β―HSD1を標的とする単離されたsiNA化合物。
- 配列番号62から122の群から選択されるヌクレオチド配列を含む、11β―HSD1を標的とする単離されたsiNA化合物。
- 前記siNAがsiRNAである、請求項20または21に記載の単離されたsiNA化合物。
- 前記siRNAがdsRNAである、請求項22に記載の単離されたsiNA化合物。
- 前記siRNAがshRNAである、請求項22に記載の単離されたsiNA化合物。
- 修飾オリゴヌクレオチドを含む、請求項20から24のいずれか一項に記載の単離されたsiNA化合物。
- 3’オーバーハングをさらに含む、請求項20から25のいずれか一項に記載の単離されたsiNA化合物。
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JP2022000035A (ja) * | 2015-09-08 | 2022-01-04 | シレンティス・エセ・ア・ウ | NRARP遺伝子の発現を阻害するためのsiRNA、並びにそのための方法及び組成物におけるそれらの使用 |
JP7394815B2 (ja) | 2015-09-08 | 2023-12-08 | シレンティス・エセ・ア・ウ | NRARP遺伝子の発現を阻害するためのsiRNA、並びにそのための方法及び組成物におけるそれらの使用 |
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CA2627272C (en) | 2015-12-01 |
JP2013176395A (ja) | 2013-09-09 |
WO2007049074A3 (en) | 2007-08-02 |
HK1120830A1 (en) | 2009-04-09 |
EP1941037A2 (en) | 2008-07-09 |
CN101346467B (zh) | 2013-03-13 |
JP5398262B2 (ja) | 2014-01-29 |
WO2007049074A2 (en) | 2007-05-03 |
CN101346467A (zh) | 2009-01-14 |
MX2008005409A (es) | 2008-11-26 |
RU2420582C2 (ru) | 2011-06-10 |
ES2403305T3 (es) | 2013-05-17 |
US8188057B2 (en) | 2012-05-29 |
RU2008120702A (ru) | 2009-12-10 |
EP2354229A2 (en) | 2011-08-10 |
CA2627272A1 (en) | 2007-05-03 |
AU2006307690A1 (en) | 2007-05-03 |
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