JPH08503856A - 相同組み換えによる内因性遺伝子の発現の活性化及び増幅 - Google Patents
相同組み換えによる内因性遺伝子の発現の活性化及び増幅Info
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- JPH08503856A JPH08503856A JP6513496A JP51349694A JPH08503856A JP H08503856 A JPH08503856 A JP H08503856A JP 6513496 A JP6513496 A JP 6513496A JP 51349694 A JP51349694 A JP 51349694A JP H08503856 A JPH08503856 A JP H08503856A
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.脊椎動物細胞のゲノムDNA中の内因性遺伝子であって得られたままの該細 胞内では発現されないかもしくは得られたままの該細胞内では明確なレベルでは 発現されないものの発現を活性化する方法並びに該遺伝子を増幅する方法であっ て、下記の工程を含む方法: a)次のものを含むDNA配列で細胞をトランスフェクトし、それによって該D NA配列を含有する細胞を作成する工程、 1)次のものからなる群より選択される内因性DNA: a)該細胞内に存在するある配列を修復し、変更し、欠失させもしくは 置換するDNA配列、もしくは b)得られたままの細胞内では内因性遺伝子に正常には機能的に連結し ていない調節配列であるDNA配列、 2)該細胞内における予め選択された部位のゲノムDNA配列と相同なDN A配列、および 3)選択マーカーをコードしている増幅可能なDNA、 b)(a)で作成された細胞を、ゲノムDNA配列に相同なDNA配列とゲノム DNA配列との間の相同組換えが起こるのに適した条件下に保持し、それによっ てゲノムDNAに 組み込まれた(a)(1)、(a)(2)および(a)(3)のDNA配列、お よび内因性遺伝子に機能的に連結した(a)(1)の外因性DNAを有する脊椎 動物起原の相同組換え細胞を作成する工程、並びに c)(b)で作成された相同組換え細胞を、選択マーカーをコードする増幅可能 なDNAの増幅を選択させる条件下で培養し、これにより選択マーカーをコード する増幅可能なDNAと(a)(1)の外因性DNAに機能的に連結した内因性 遺伝子とを共増幅し、 それによって、選択マーカーをコードする増幅されたDNAおよびそれと共増幅 された(a)(1)のDNA配列に機能的に連結した内因性遺伝子とを含有する 相同組換え細胞であって細胞内で共増幅された該遺伝子が発現しているものを作 成する工程。 2.脊椎動物起原の細胞のゲノムDNAにDNA配列をターゲティングする方法 であって、下記の工程を含む方法、 a)以下のものを含むDNA構築物を供給する工程、 1)脊椎動物起原の細胞内で発現させようとする産物をコードする外因性D NA: 2)脊椎動物起原の細胞内のゲノムDNA配列に相同なDNA配列、および 3)それを指標として増幅コピーの選択を実施できるようなマーカーをコー ドする増幅可能なDNA配列、 b)(a)で供給されたDNA構築物を脊椎動物起原の細胞中に導入し、それに より(a)で供給されたDNA構築物を含む細胞を作成する工程、 c)(b)で作成された細胞を、ゲノムDNA配列に相同なDNA配列とゲノム DNA配列との間で相同組換えが起こるのに適した条件下に保持し、それにより 該細胞のゲノムDNA中に組み込まれた(a)のDNA構築物を有する脊椎動物 起原の相同組換え細胞を作成する工程、 d)(b)で作成された相同組換え細胞を、選択マーカーをコードする増幅可能 なDNAの増幅を選択させる条件下で培養し、これにより選択マーカーをコード する増幅可能なDNAおよび(a)(1)の外因性DNAを共増幅させ、それに より選択マーカーをコードする増幅されたDNAと共増幅された外因性遺伝子と を含有する相同組換え細胞であって、共増幅された外因性遺伝子を発現すること ができる細胞を作成する工程。 3.該脊椎動物細胞が一次細胞または二次細胞である請求項1または請求項2記 載の方法。 4.該一次細胞または二次細胞が哺乳類細胞である請求項3記載の方法。 5.該一次細胞または二次細胞がヒトの細胞である請求項3記載の方法。 6.該脊椎動物細胞が不死化細胞(immortalized cell)である請求項1または 請求項2記載の方法。 7.該不死化細胞が哺乳類起原のものである請求項6記載の方法。 8.該不死化細胞がヒト起原のものである請求項6記載の方法。 9.選択マーカーをコードする増幅可能なDNAが、ジヒドロフォレートリダク ターゼ、アデノシンデアミナーゼ、およびCADからなる群より選択される選択 マーカーをコードするものである請求項1〜請求項8いずれか1項に記載の方法 。 10.該DNA構築物がさらに(a)付加的なポジティブ選択マーカー、(b) ネガティブ選択マーカーまたは(c)付加的なポジティブ選択マーカーとネガテ ィブ選択マーカーを含むものである請求項1〜請求項9いずれか1項に記載の方 法。 11.該付加的なポジティブ選択マーカーがneoである請求項10記載の方法 。 12.該ポジティブ選択マーカーがneoであり、該ネガテ ィブ選択マーカーがgptまたはHSV−TK遺伝子である請求項10記載の方 法。 13.発現させるべき遺伝子が、ホルモン、サイトカイン、抗原、抗体、酵素、 凝固因子、輸送タンパク質、受容体、調節タンパク質、構造タンパク質、転写因 子、アンチセンスRNAおよびリボザイム、並びに自然に現れないタンパク質や 核酸からなる群より選択される産物をコードするものである請求項1〜請求項1 2いずれか1項記載の方法。 14.該内因性遺伝子がヒト成長ホルモン、ヒトインスリン、ヒトインスリノト ロピン、およびヒトエリスロポエチンからなる群より選択される治療目的の産物 をコードするものである請求項1〜請求項12いずれか1項記載の方法。 15.前記請求項のいずれか1項記載の方法により作成される相同組換え細胞。 16.発現させるべき内因性遺伝子または外因性遺伝子が治療目的の産物をコー ドするものである請求項1〜請求項8いずれか1項記載の方法。 17.DNA構築物が(a)付加的なポジティブ選択マーカー、(b)ネガティ ブ選択マーカーまたは(c)付加的なポジティブ選択マーカーとネガティブ選択 マーカーをさらに含 むものである請求項16記載の方法。 18.付加的なポジティブ選択マーカーがneoである請求項17記載の方法。 19.ポジティブ選択マーカーがneoであり、ネガティブ選択マーカーがgp tまたはHSV−TK遺伝子である請求項17記載の方法。 20.発現させるべき遺伝子が、ホルモン、サイトカイン、抗原、抗体、酵素、 凝固因子、輸送タンパク質、受容体、調節タンパク質、構造タンパク質、転写因 子、アンチセンスRNAおよびリボザイム、並びに自然に現れないタンパク質や 核酸からなる群より選択される産物をコードするものである請求項16〜請求項 19いずれか1項記載の方法。 21.内因性遺伝子または外因性遺伝子がヒト成長ホルモン、ヒトインスリン、 ヒトインスリノトロピン、およびヒトエリスロポエチンからなる群より選択され る治療目的の産物をコードするものである請求項20記載の方法。 22.請求項16〜請求項21のいずれか1項記載の方法により作成される相同 組換え細胞。 23.請求項1〜請求項5および請求項9〜請求項14のい ずれか1項に記載の方法により作成され、治療例え哺乳類またはヒトの治療上の 用途を有する一次細胞または二次細胞。 24.請求項1〜請求項5および請求項9〜請求項14のいずれか1項に記載の 方法により作成される細胞の、遺伝子治療に使用する治療剤の製造のための使用 。 25.哺乳類内に導入するように適合させられ、かつ、請求項16記載の方法に より作成された細胞を閉じ込める遮蔽装置(a barrier device)であって、該装 置は、それが哺乳類内に導入されると治療目的の産物を哺乳類の循環系又は組織 へ移行させるが脊椎動物細胞が該遮蔽装置の外で増殖するのを防止し、その哺乳 類の免疫系により該細胞が拒絶されるのを防止するような物質から作られている 、遮蔽装置。 26.請求項16の方法により作成された哺乳類細胞中に導入することを含む、 哺乳類に治療目的の産物の有効量を供給する方法であって、該細胞は遮蔽装置内 に閉じ込められて哺乳類に導入され、該遮蔽装置は該哺乳類の循環系または組織 へ該治療産物を移行せしめるが、脊椎動物細胞の遮蔽装置外での増殖を妨げ、哺 乳類の免疫系により該細胞が拒絶されるのを防止するような物質で作られるもの である方法。 27.請求項16の方法により作成された哺乳類細胞中に導 入することを含む、哺乳類に治療目的の産物の有効量を供給する方法。 28.請求項16の方法により作成されたヒト細胞中に導入することを含む、ヒ トに治療目的の産物の有効量を供給する方法。 29.治療目的のタンパク質の発現に適した条件下で請求項9記載の相同組換え 細胞を培養することを含む、治療目的のタンパク質のインビトロ生産方法であっ て、該治療目的のタンパク質が請求項9記載の細胞により発現されるものである 方法。 30.治療目的のタンパク質をコードするヒト遺伝子のイントロンレス コピー を含む微生物細胞を用いる、治療目的のタンパク質のインビトロ生産方法であっ て、下記の工程を含む方法、 a)ヒト細胞中へ以下のものを含むDNA構築物を導入し、それにより該DNA 構築物を含む細胞を作成する工程、 1)レトロウイルスのLTR、 2)微生物細胞における選択マーカーをコードする遺伝子、 3)微生物細胞における治療目的のタンパク質の発現を増強できる調節配列 、 4)微生物細胞における治療目的のタンパク質の分 泌を増強できるリーダーペプチドをコードするDNA、 5)治療目的のタンパク質の第1アミノ酸をコードするDNAに隣接しかつ その上流にあるヒトゲノムDNA配列とDNA構築物との相同組換えを指示させ るのに充分な配列。 b)(a)で作成された細胞を、ゲノムDNA配列に相同なDNA配列とゲノム DNA配列との間で相同組換えが起こるのに適した条件下に保持し、それにより 、治療目的のタンパク質をコードする遺伝子に隣接しかつその上流に位置しそし てそれと機能的に連結しているゲノムDNA中に組み込まれた(a)のDNA構 築物を有する相同組換え細胞を作成する工程、 c)(b)で作成された相同組換え細胞中に以下のものを含むDNA構築物を導 入する工程であって、それにより該ゲノムDNA中に(a)のDNA構築物を組 み込みかつ(c)のDNA構築物を含む相同組換え細胞を作成する工程、 1)微生物細胞における転写終止を指示することができるDNA配列、 2)微生物細胞におけるDNA複製を指示することができるDNA配列、 3)レトロウイルスのLTR、 4)治療目的のタンパク質の終止コドンの下流にあるヒトゲノムDNA配列 とDNA構築物との相同組換えを指示するのに充分な配列、 d)(c)で作成された細胞を、ゲノムDNA配列に相同なDNA配列とゲノム DNA配列との間の相同組換えが起こるのに適した条件下で保持し、それにより 、治療目的のタンパク質をコードする遺伝子の上流に位置しかつそれと機能的に 連結したゲノムDNA中に組み込まれた(a)のDNA構築物を有し、そして治 療目的のタンパク質をコードする遺伝子の下流に組み込まれかつ機能的にそれと 連結しているDNA構築物(c)をも有する相同組換え細胞を作成する工程、 e)(d)で作成された細胞を、(a)および(c)で導入されたLTRs間に あるDNA配列のRNA産物の、レトロウイルスLTRにより指示される転写、 プロセッシング、および逆転写に適した条件下で培養し、それにより、(a)で 述べたDNA構築物を含むDNA配列に作用的にリンクしており、かつ、(c) で述べたDNA構築物を含むDNA配列に作用的にリンクしている治療目的のタ ンパク質をコードする遺伝子のイントロンレスDNAコピーを含むDNA配列を 作成する工程、この配列はここではイントロンレスDNA配列と呼ぶ、 f)(e)で作成されたイントロンレスDNA配列を細胞から分離する工程、 g)(f)で分離されたDNAを微生物細胞に導入し、それにより(e)で作成 されたDNAを含む微生物細胞を作成する工程、 h)(a)で述べたDNA構築物中に存在する選択マーカ ーを選択する選択剤の存在下に(g)で作成された微生物細胞を培養する工程、 i)微生物細胞中の治療目的のタンパク質の発現および分泌に適した条件下で、 (h)で作成した細胞を培養し、それにより微生物細胞中で治療目的のタンパク 質を生産し、そしてそれから該タンパク質を分泌させる工程、並びに j)(i)で生産された治療目的のタンパク質を微生物細胞から分離する工程。 31.該微生物細胞がサッカロミセス セレビシエ(Saccharomyces cerevisiae )、または大腸菌である請求項30記載の方法。 32.細胞内に存在する発現させるべき遺伝子であって、得られたままの細胞内 では発現しないか得られたままの細胞内では明確なレベルで発現しないものの発 現を作動させる方法であって、相同組換えに適した条件の下に調節領域を含むD NA構築物を該細胞に導入することを含む方法であり、該調節領域は発現させる べき遺伝子の調節領域に挿入されまたはその全部または一部を置換し、そして発 現されるべき遺伝子に機能的に連結しているものであり、これにより該遺伝子を 発現する相同組換え細胞を作成する方法。 33.得られたままの細胞が不死化細胞である請求項32記載の方法。
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JP2001511341A (ja) * | 1997-07-23 | 2001-08-14 | ロシュ ダイアグノスティックス ゲーエムベーハー | ヒト細胞におけるヒト変異型タンパク質の相同的組換えによる生産 |
JP2001511343A (ja) * | 1997-07-23 | 2001-08-14 | ロシュ ダイアグノスティックス ゲーエムベーハー | 内因性遺伝子活性化によるエリスロポエチンの製造 |
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DE69334340D1 (de) | 2010-09-23 |
NZ329348A (en) | 1999-10-28 |
WO1994012650A2 (en) | 1994-06-09 |
KR100364916B1 (ko) | 2003-03-31 |
NZ259165A (en) | 1998-01-26 |
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EP0672160B1 (en) | 2010-08-11 |
IL107822A (en) | 2007-05-15 |
DK0672160T3 (da) | 2010-11-29 |
EP0672160B8 (en) | 2010-09-22 |
MX9307623A (es) | 1994-06-30 |
WO1994012650A3 (en) | 1994-08-04 |
ATE477327T1 (de) | 2010-08-15 |
TW402639B (en) | 2000-08-21 |
AU689455B2 (en) | 1998-04-02 |
JP2005027673A (ja) | 2005-02-03 |
CA2151032A1 (en) | 1994-06-09 |
SG46476A1 (en) | 1998-02-20 |
NZ336200A (en) | 2000-12-22 |
AU5736294A (en) | 1994-06-22 |
EP0672160A1 (en) | 1995-09-20 |
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