JP4209678B2 - 標的遺伝子の発現を阻害する方法および腫瘍を治療するための医薬 - Google Patents
標的遺伝子の発現を阻害する方法および腫瘍を治療するための医薬 Download PDFInfo
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Description
さらに、本発明は、少なくとも1つの標的遺伝子の発現を阻害するための少なくとも1つの二本鎖リボ核酸(dsRNA)を含有する腫瘍疾患を治療するための医薬に関し、ここで、dsRNAのS1鎖は、標的遺伝子に対して少なくとも部分的に相補的な25個未満の連続したヌクレオチドからなる領域を有する。ここで、標的遺伝子は、それが発現することによって、腫瘍細胞でのアポトーシスを阻害または阻止する遺伝子である。医薬の投与量は、少なくとも1つの標的遺伝子の発現が、阻害され得るようなものである。驚くべきことに、そのような医薬は、非常に低用量で使用され得ることが示されている。1日当たり、1kg体重当たり5mgのdsRNAの投与量は、腫瘍細胞での標的遺伝子の発現の阻害または完全な抑制に十分である。このような投与量では、副作用は大幅に回避される。
S2:5’− cag gac cuc gcc gcu gca gac c−3’(配列番号1)
S1:3’−cg guc cug gag cgg cga cgu cug g−5’(配列番号2)
dsRNA 2は、ヒトBcl−2遺伝子の第2の配列に相補的である。
S2:5’− g ccu uug ugg aac ugu acg gcc−3’(配列番号3)
S1:3’−uac gga aac acc uug aca ugc cgg−5’(配列番号4)
dsRNA 3は、ネオマイシン抵抗性遺伝子の配列に相補的である。
S2:5’− c aag gau gag gau cgu uuc gca−3’(配列番号5)
S1:3’−ucu guc cua cuc cua gca aag cg−5’(配列番号6)
トランスフェクションを、オリゴフェクタミン(Invitrogen Corp.,Karlsruhe)と共に6−ウェルプレートで行った。250,000個の細胞を、各ウェルに配置した。二本鎖のオリゴリボヌクレオチドのトランスフェクションを、Invitrogenが推奨するオリゴフェクタミン用のプロトコルに従って行った(データは6−ウェルプレートの1ウェルに関する)。
Claims (16)
- 培養した腫瘍細胞のアポトーシスを阻害または阻止する少なくとも1つの標的遺伝子の発現を阻害する方法であって、少なくとも1つの二本鎖リボ核酸(dsRNA)が、前記培養した腫瘍細胞中に導入され、ここで当該dsRNAのS1鎖は、前記標的遺伝子に対して少なくとも部分的に相補的な19〜24個の連続したヌクレオチドからなる領域を有し、前記S1鎖の3’末端に位置するdsRNAの末端のみが、当該S1鎖の3’末端で1〜4個のヌクレオチドからなる一本鎖オーバーハングを有し、
前記標的遺伝子が、Bcl−2ファミリーに属する少なくとも1つの遺伝子であることを特徴とする、方法。 - 前記一本鎖のオーバーハングは、2個または3個のヌクレオチドからなる、請求項1に記載の方法。
- 前記dsRNAの少なくとも一端は、前記培養した腫瘍細胞中での破壊また分離に対抗するために修飾される、請求項1または2に記載の方法。
- 相補的なヌクレオチド対によって生じる前記dsRNAの結合は、少なくとも1つの他の化学結合によって増加する、請求項1〜3のいずれかに記載の方法。
- 前記dsRNAは、添付の配列表の、配列番号1を有するS2鎖および配列番号2を有するS1鎖、または配列番号3を有するS2鎖および配列番号4を有するS1鎖からなる、請求項1〜4のいずれかに記載の方法。
- 前記培養した腫瘍細胞は膵臓ガン細胞である、請求項1〜5のいずれかに記載の方法。
- 前記dsRNAは、当該dsRNAを囲むミセル構造、リポソーム、または当該dsRNAを囲むカプシドによって、前記培養した腫瘍細胞中に導入される、請求項1〜6のいずれかに記載の方法。
- 腫瘍疾患を治療する医薬であって、腫瘍細胞のアポトーシスを阻害または阻止する少なくとも1つの標的遺伝子の発現を阻害する少なくとも1つの二本鎖リボ核酸(dsRNA)を含み、前記dsRNAのS1鎖は、前記標的遺伝子に対して少なくとも部分的に相補的な19〜24個の連続したヌクレオチドからなる領域を有し、前記S1鎖の3’末端に位置するdsRNAの末端のみが、当該S1鎖の3’末端で1〜4個のヌクレオチドからなる一本鎖オーバーハングを有し、
前記標的遺伝子が、Bcl−2ファミリーに属する少なくとも1つの遺伝子であることを特徴とする、医薬。 - 前記一本鎖のオーバーハングは、2個または3個のヌクレオチドからなる、請求項8に記載の医薬。
- 前記dsRNAの少なくとも一端は、腫瘍細胞中での破壊また分離に対抗するために修飾される、請求項8または9に記載の医薬。
- 相補的なヌクレオチド対によって生じる前記dsRNAの結合は、少なくとも1つの他の化学結合によって増加する、請求項9〜10のいずれかに記載の医薬。
- 前記dsRNAは、添付の配列表の、配列番号1を有するS2鎖および配列番号2を有するS1鎖、または配列番号3を有するS2鎖および配列番号4を有するS1鎖からなる、請求項9〜11のいずれかに記載の医薬。
- 前記腫瘍細胞は膵臓ガン細胞である、請求項9〜12のいずれかに記載の医薬。
- 前記dsRNAは、溶液中に存在するか、ミセル構造、リポソーム、もしくはカプシドによって囲まれて医薬の中に存在する、請求項9〜13のいずれかに記載の医薬。
- 前記医薬は、吸入、経口摂取、静脈内注射、腹腔内注射、または腫瘍細胞への直接注射に適した製剤である、請求項9〜14のいずれかに記載の医薬。
- 前記製剤は、dsRNAと生理学的耐容性を有する緩衝液とからなる、請求項15に記載の医薬。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10100586A DE10100586C1 (de) | 2001-01-09 | 2001-01-09 | Verfahren zur Hemmung der Expression eines Ziegens |
PCT/EP2002/000151 WO2002055692A2 (de) | 2001-01-09 | 2002-01-09 | Verfahren zur hemmung der expression eines zielgens und medikament zur therapie einer tumorerkrankung |
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JP2004519457A JP2004519457A (ja) | 2004-07-02 |
JP4209678B2 true JP4209678B2 (ja) | 2009-01-14 |
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JP2002556739A Expired - Lifetime JP4209678B2 (ja) | 2001-01-09 | 2002-01-09 | 標的遺伝子の発現を阻害する方法および腫瘍を治療するための医薬 |
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Country | Link |
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US (1) | US7473525B2 (ja) |
EP (3) | EP2213736B1 (ja) |
JP (1) | JP4209678B2 (ja) |
CN (1) | CN1650010A (ja) |
AT (1) | ATE460481T1 (ja) |
CA (1) | CA2432341A1 (ja) |
DE (2) | DE10100586C1 (ja) |
ES (1) | ES2204360T3 (ja) |
WO (1) | WO2002055692A2 (ja) |
ZA (2) | ZA200304127B (ja) |
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US20040203024A1 (en) * | 1996-06-06 | 2004-10-14 | Baker Brenda F. | Modified oligonucleotides for use in RNA interference |
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DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
US7601494B2 (en) | 1999-03-17 | 2009-10-13 | The University Of North Carolina At Chapel Hill | Method of screening candidate compounds for susceptibility to biliary excretion |
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DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
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KR101215789B1 (ko) * | 2000-03-30 | 2012-12-26 | 화이트헤드 인스티튜트 포 바이오메디칼 리서치 | Rna 간섭의 rna 서열 특이적인 매개체 |
CZ302719B6 (cs) | 2000-12-01 | 2011-09-21 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Izolovaná molekula dvouretezcové RNA, zpusob její výroby a její použití |
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CA2432341A1 (en) | 2002-07-18 |
ZA200304500B (en) | 2003-11-18 |
CN1650010A (zh) | 2005-08-03 |
EP1349927B1 (de) | 2010-03-10 |
ZA200304127B (en) | 2004-05-11 |
ES2204360T1 (es) | 2004-05-01 |
EP2213736A2 (de) | 2010-08-04 |
US20040001811A1 (en) | 2004-01-01 |
WO2002055692A2 (de) | 2002-07-18 |
JP2004519457A (ja) | 2004-07-02 |
DE50214266D1 (de) | 2010-04-22 |
ATE460481T1 (de) | 2010-03-15 |
ES2204360T3 (es) | 2010-07-06 |
EP2365075A1 (de) | 2011-09-14 |
EP2213736B1 (de) | 2018-03-07 |
US7473525B2 (en) | 2009-01-06 |
WO2002055692A3 (de) | 2003-06-12 |
EP1349927A2 (de) | 2003-10-08 |
DE10100586C1 (de) | 2002-04-11 |
EP2213736A3 (de) | 2010-09-01 |
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