JP2017522875A - 修飾抗mir−138オリゴヌクレオチド - Google Patents
修飾抗mir−138オリゴヌクレオチド Download PDFInfo
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- JP2017522875A JP2017522875A JP2017502244A JP2017502244A JP2017522875A JP 2017522875 A JP2017522875 A JP 2017522875A JP 2017502244 A JP2017502244 A JP 2017502244A JP 2017502244 A JP2017502244 A JP 2017502244A JP 2017522875 A JP2017522875 A JP 2017522875A
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Abstract
Description
本出願は、2014年7月31日に提出されたシンガポール特許出願第10201404535S号による優先権の利益を主張するものであり、本明細書においてその内容全体がすべての目的に対して引用により援用される。
非限定的な例および添付の表とともに考慮されるとき、詳細な説明を参照することによって本発明がよりよく理解されるだろう。
マイクロRNA(miRNA)は長い間、多くの発生および細胞のプロセスにおける遺伝子発現の重要な転写後制御因子であると考えられてきた。加えていくつかのmiRNAは、たとえば癌などの増殖性疾患の開始および進行に関連付けられている。よって、miRNA発現を制御できる分子は、増殖性疾患などの特定の疾患の制御に対して有利である。
材料および方法
細胞培養:U87MG細胞系を、10%FBS、ピルビン酸ナトリウム(ギブコ(Gibco))、L−グルタミン酸(ギブコ)およびPen−Strep(ギブコ)を補ったMEM培地(ギブコ)中で、37℃に維持した5%CO2インキュベーター内で培養する。0.25%トリプシン(ギブコ)を用いて、細胞を75%の集密度にて継代した。
Claims (28)
- 少なくとも1つのロックド核酸(LNA)を含むオリゴヌクレオチドであって、
前記オリゴヌクレオチドはmiR−138のヌクレオチド配列に対して実質的に相補的であり、
前記オリゴヌクレオチドは1つまたはそれ以上のmiR−138の活性を低減または阻害する、オリゴヌクレオチド。 - 前記ロックド核酸は、リボースの立体構造をロックする二環構造を生成する、請求項1に記載のオリゴヌクレオチド。
- 前記二環構造は、2’酸素を4’炭素に接続する架橋を生成するリボース部分の修飾によって生成される、請求項2に記載のオリゴヌクレオチド。
- 前記架橋は、エチレン、メチレン、またはオキシメチレン架橋である、請求項3に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、細胞酵素による分解に抵抗する修飾をさらに含む、請求項1から4のいずれか一項に記載のオリゴヌクレオチド。
- 前記修飾は、少なくとも1つのホスホロチオエート連結による修飾である、請求項5に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドの5’末端および3’末端のみがホスホロチオエート連結によって修飾され、前記オリゴヌクレオチドの中間部分はホスホロチオエート連結によって修飾されない、請求項6に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは約11ヌクレオチドから23ヌクレオチドの長さである、請求項1から7のいずれか一項に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは少なくとも2つのロックド核酸を含有する、請求項8に記載のオリゴヌクレオチド。
- 非ロックド核酸は、2から4の連続した核酸として少なくとも2回含まれる、請求項1から9のいずれか一項に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、2または3または4以上の連続したロックド核酸を有する一続きの核酸を含有しない、請求項1から10のいずれか一項に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは少なくとも1つのホスホロチオエート連結を有する、請求項1から10のいずれか一項に記載のオリゴヌクレオチド。
- 前記ホスホロチオエート連結は、互いに独立に、前記オリゴヌクレオチドの3’末端および/または5’末端の少なくとも1に含まれる、請求項12に記載のオリゴヌクレオチド。
- 前記オリゴヌクレオチドは、塩基加水分解およびヌクレアーゼに対する安定性を与える修飾をさらに含む、請求項1から13のいずれか一項に記載のオリゴヌクレオチド。
- 前記修飾は、非ロックド核酸のリボース部分の2−ヒドロキシル基に2’−O−デオキシ、2’−O−メチル、2’−O−アルキル、2’−ハロ、または2’−フルオロを付加するステップを含む、請求項14に記載のオリゴヌクレオチド。
- 配列5’−CGGCCUGAUTCACAACACCAGCU−3’(配列番号2;抗mRNA−138)、および5’−CGGCCUGAUUCACAACACCAGCU−3’(配列番号3;抗mRNA−138)を含み、配列番号2および配列番号3は独立に少なくとも1つのロックド核酸を含む、請求項1から15のいずれか一項に記載のオリゴヌクレオチド。
- 前記ロックド核酸は、配列番号2の位置3、5、8、10、12、15、17、19および21にあり、ここで配列番号2の位置1は5’末端であり、配列番号2の位置23は3’末端である、請求項16に記載のオリゴヌクレオチド。
- 前記ホスホロチオエート連結は、配列番号2の位置1から5、または19から23より独立に選択される、請求項17に記載のオリゴヌクレオチド。
- 前記ホスホロチオエート連結は、配列番号2の位置1、2、3、20、21、および23にある、請求項18に記載のオリゴヌクレオチド。
- 前記修飾は、配列番号2の位置1、2、4、6、7、9、11、13、14、16、18、20、22、23における2’−O−メチル化である、請求項19に記載のオリゴヌクレオチド。
- 5’−mC*mG*G*mCCmUmGAmUTmCAmCmAAmCAmCCmA*G*mC*mU−3’(配列番号13)、5’−mC*mG*G*mCmCTmGmATmUmCAmCmAAmCmACmCmA*G*mC*mU−3’(配列番号12)、および5’−mC*mG*mG*mCmCTmGAmUTmCAmCAmACmACmCmA*mG*mC*mU−3’(配列番号10)からなる群より選択される配列の1つまたはそれ以上を含み、ここでmは2’−O−メチル化であり、*はホスホロチオエート結合であり、下線付きのヌクレオチドはロックド核酸修飾を表す、請求項1から20のいずれか一項に記載のオリゴヌクレオチド。
- 配列5’−A*C*AACACCAG*C*−3’(配列番号5)を含み、ここで*はホスホロチオエート結合であり、下線付きのヌクレオチドはロックド核酸修飾を表す、請求項1から10のいずれか一項に記載のオリゴヌクレオチド。
- 有効量の、請求項1から22のいずれか一項に記載のオリゴヌクレオチド、またはその薬学的に許容できる塩と、薬学的に許容できる担体または希釈剤とを含む、医薬組成物。
- 処置を必要とする対象における増殖性疾患を処置する方法であって、請求項1から22のいずれか一項に記載のオリゴヌクレオチドを前記対象に投与するステップを含む、方法。
- 前記増殖性疾患は良性の腫瘍または癌である、請求項24に記載の方法。
- 前記癌は、悪性神経膠腫および乳癌からなる群より選択される、請求項25に記載の方法。
- 処置を必要とする対象において増殖性疾患を処置するための薬物の製造における、請求項1から22のいずれか一項に記載のオリゴヌクレオチドの使用。
- 細胞内のmiR−138の活性を低減または阻害する方法であって、請求項1〜22のいずれか一項に記載のオリゴヌクレオチドに前記細胞を接触させるステップを含む、方法。
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JP2009532392A (ja) * | 2006-04-03 | 2009-09-10 | サンタリス ファーマ アー/エス | antimiRNAアンチセンスオリゴヌクレオチドを含む医薬組成物 |
WO2012087242A1 (en) * | 2010-12-20 | 2012-06-28 | Agency For Science, Technology And Research | Targeting glioma stem cells by sequence-specific functional inhibition of pro-survival oncomir-138 |
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WO2012087242A1 (en) * | 2010-12-20 | 2012-06-28 | Agency For Science, Technology And Research | Targeting glioma stem cells by sequence-specific functional inhibition of pro-survival oncomir-138 |
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