JPH08504562A - ウシ種による組み換えポリペプチドの製造及びトランスジェニック法 - Google Patents
ウシ種による組み換えポリペプチドの製造及びトランスジェニック法Info
- Publication number
- JPH08504562A JPH08504562A JP6501794A JP50179494A JPH08504562A JP H08504562 A JPH08504562 A JP H08504562A JP 6501794 A JP6501794 A JP 6501794A JP 50179494 A JP50179494 A JP 50179494A JP H08504562 A JPH08504562 A JP H08504562A
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- sequence
- transgene
- bovine
- recombinant
- transgenic
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Abstract
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- 【特許請求の範囲】 1.トランスジェニックウシ種中で組み換えポリペプチドを製造するためのトラ ンスジーンであって、該ウシ種の少なくとも一つの細胞タイプ中で機能しうる、 組み換えポリペプチドをエンコードする組み換えDNAに操作可能に連結された 少なくとも一つの発現調節DNA配列を含むトランスジーンにおいて、該トラン スジーンは、該組み換えポリペプチドを製造するために、該トランスジーンを含 むウシ種の少なくとも一つの該細胞タイプ中で該組み換えDNA配列の発現を引 き起こすことができるトランスジーン。 2.該発現調節配列が血清アルブミンからの5′及び3′発現調節配列を含み、 該細胞タイプが肝臓細胞であり、該組み換えポリペプチドがヒト血清アルブミン であり、そして、該トランスジーンが更に該肝臓細胞中で機能できかつ該ヒト血 清アルブミンをエンコードする組み換えDNAに操作可能に連結されている分泌 DNA配列を含むところの、請求の範囲第1項のトランスジーン。 3.トランスジェニックウシ種のミルク中で組み換えポリペプチドを製造するた めのトランスジーンであって、該ウシ種の乳房分泌細胞中で機能できる少なくと も一つの発現調節DNA配列、該ウシ種の乳房分泌細胞中で機能できる分泌シグ ナル配列をエンコードする分泌DNA配列及び組み換えポリペプチドをエンコー ドする組み換えDNA配列を含むトランスジーンにおいて、該分泌DNA配列は 該組み換えDNA配列に操作可能に連結されて分泌−組み換え DNA配列を形成し、そして該少なくとも一つの発現調節配列は該分泌−組み換 えDNA配列に操作可能に連結されており、このようにして、該トランスジーン は該トランスジーンを含むウシ種の乳房分泌細胞中で該分泌−組み換えDNA配 列の発現を引き起こすことができて、該乳房分泌細胞から分泌されたときに、該 ウシ種のミルク中に組み換えポリペプチドを製造する組み換えポリペプチドの形 を製造するところのトランスジーン。 4.更に組み換え介在配列を含む請求の範囲第1項又は第3項のトランスジーン 。 5.該組み換え介在配列がハイブリッド介在配列である請求の範囲第4項のトラ ンスジーン。 6.該ハイブリッド介在配列が許容されうるRNAスプライスシグナルを含む請 求の範囲第5項のトランスジーン。 7.該組み換えポリペプチドがウシ種からの同種ポリペプチドである請求の範囲 第3項のトランスジーン。 8.該同種ポリペプチドが、カゼイン、ラクトフェリン、リゾチーム、コレステ ロール加水分解酵素及び血清アルブミンからなる群より選ばれる請求の範囲第7 項のトランスジーン。 9.該組み換えポリペプチドが異種ポリペプチドである請求の範囲第3項のトラ ンスジーン。 10.該異種ポリペプチドが、ヒトミルクタンパク質、ヒト血清タンパク質及び工 業的酵素からなる群より選ばれる請求の範囲第9項のトランスジーン。 11.該異種ポリペプチドがヒトミルクタンパク質である請求の範囲第10項のトラ ンスジーン。 12.該ヒトミルクタンパク質が、分泌免疫グロブリン、リゾチーム、ラクトフェ リン、ラクトグロブリン、α−ラクトアルブミン及び胆汁塩に刺激されたリパー ゼからなる群より選ばれる請求の範囲第11項のトランスジーン。 13.該ミルクタンパク質がラクトフェリン又はリゾチームである請求の範囲第12 項のトランスジーン。 14.該異種ポリペプチドがヒト血清タンパク質である請求の範囲第10項のトラン スジーン。 15.該ヒト血清タンパク質が、アルブミン、免疫グロブリン、因子VIII、因子IX 及びプロテインCからなる群より選ばれる請求の範囲第14項のトランスジーン。 16.該血清タンパク質がアルブミンである請求の範囲第15項のトランスジーン。 17.該異種ポリペプチドが、プロテアーゼ、リパーゼ、キチナーゼ及びリグニナ ーゼ(ligninase)からなる群より選ばれる工業的酵素である請求の範囲第10項 のトランスジーン。 18.該分泌DNA配列が、ヒトラクトフェリン、ヒト血清アルブミン、ヒトリゾ チームからの分泌シグナル配列及びウシαS1−カゼイン、αS2−カゼイン、 β−カゼイン、κ−カゼイン、α−ラクトアルブミン、β−ラクトグロブリン及 び血清アルブミンからの分泌シグナル配列をエンコードするDNA配列からなる 群より選ばれる請求の範囲第 3項のトランスジーン。 19.該分泌DNA配列がウシαS1カゼインのシグナル分泌配列をエンコードす るDNA配列である請求の範囲第18項のトランスジーン。 20.該少なくとも一つの発現調節配列が、該分泌−組み換えDAN配列の5′末 端に操作可能に連結された5′発現調節DNA配列を含む、請求の範囲第3項の トランスジーン。 21.該5′発現調節DNA配列が、αS1−カゼイン、αS2−カゼイン、β− カゼイン、κ−カゼイン、α−ラクトアルブミン及びβ−ラクトグロブリンをエ ンコードするウシ遺伝子からの5′発現調節配列からなる群より選ばれる請求の 範囲第20項のトランスジーン。 22.該5′発現調節DNA配列が、ウシαS1−カゼインのプロモーターを含む 近位5′発現調節配列である請求の範囲第21項のトランスジーン。 23.該5′発現調節DNA配列が更に、ウシαS1−カゼインからの5′−フラ ンキングDNA配列を含む遠位5′発現調節配列を含む、請求の範囲第22項のト ランスジーン。 24.該分泌−組み換えDNA配列の3′末端に操作可能に連結された3′発現調 節配列を更に含む請求の範囲第20項のトランスジーン。 25.該3′発現調節配列が、αS1−カゼイン、αS2−カゼイン、β−カゼイ ン、κ−カゼイン、α−ラクトアルブミン及びβ−ラクトグロブリンをエンコー ドするウシ遺 伝子からの3′発現調節配列を含む、請求の範囲第24項のトランスジーン。 26.該3′発現調節DNA配列が、ウシαS1−カゼインからの3′近位発現調 節配列を含む請求の範囲第25項のトランスジーン。 27.該3′発現調節配列が更に、ウシαS1−カゼインからの3′遠位発現調節 配列を含む、請求の範囲第26項のトランスジーン。 28.該遠位5′発現調節DNA配列がウシαS1−カゼインの約30kbの5′−フ ランキング領域を含み、かつ、該遠位3′発現調節DNA配列がウシαS1−カ ゼインの約15kbの3′−フランキング領域を含む、請求の範囲第27項のトランス ジーン。 29.組み換えポリペプチドをその動物の少なくとも一つの細胞タイプ中で製造で きるトランスジェニックウシ種。 30.組み換えペプチドを、そのトランスジェニック種のミルク中に製造できるト ランスジェニックウシ種。 31.該組み換えポリペプチドが、ウシ種からの同種ポリペプチドである請求の範 囲第30項のトランスジェニックウシ種。 32.該組み換えポリペプチドが異種ポリペプチドである請求の範囲第30項のトラ ンスジェニックウシ種。 33.該異種ポリペプチドが、ヒトミルクタンパク質、ヒト血清タンパク質及び工 業的酵素からなる群より選ばれる請求の範囲第32項のトランスジェニックウシ種 。 34.該異種ポリペプチドがヒトミルクタンパク質である請求の範囲第33項のトラ ンスジェニックウシ種。 35.該ヒトミルクタンパク質が、分泌免疫グロブリン、リゾチーム、ラクトフェ リン、ラクトグロブリン、α−ラクトアルブミン及び胆汁塩に刺激されたリパー ゼからなる群より選ばれる請求の範囲第34項のトランスジェニックウシ種。 36.該ミルクタンパク質がラクトフェリン又はリゾチームである請求の範囲第35 項のトランスジェニックウシ種。 37.該異種ポリペプチドがヒト血清タンパク質である請求の範囲第33項のトラン スジェニックウシ種。 38.該ヒト血清タンパク質が、アルブミン、免疫グロブリン、因子VIII、因子IX 及びプロテインCからなる群より選ばれる請求の範囲第37項のトランスジェニッ クウシ種。 39.該血清タンパク質がアルブミンである請求の範囲第38項のトランスジェニッ クウシ種。 40.該異種ポリペプチドが、プロテアーゼ、リパーゼ、キチナーゼ及びリグニナ ーゼからなる群より選ばれる工業的酵素である請求の範囲第33項のトランスジェ ニックウシ種。 41.組み換えポリペプチドを含むトランスジェニックウシ種からのミルク。 42.該組み換えポリペプチドが、ウシ種からの同種ポリペプチドである請求の範 囲第41項のミルク。 43.該組み換えポリペプチドが異種ポリペプチドである請求の範囲第41項のミル ク。 44.該異種ポリペプチドが、ヒトミルクタンパク質、ヒト血清タンパク質及び工 業的酵素からなる群より選ばれる請求の範囲第43項のミルク。 45.該異種ポリペプチドがヒトミルクタンパク質である請求の範囲第44項のミル ク。 46.該ヒトミルクタンパク質が、分泌免疫グロブリン、リゾチーム、ラクトフェ リン、ラクトグロブリン、α−ラクトアルブミン及び胆汁塩で刺激されたリパー ゼからなる群より選ばれる請求の範囲第45項のミルク。 47.該ミルクタンパク質がラクトフェリン又はリゾチームである請求の範囲第46 項のミルク。 48.該異種ポリペプチドがヒト血清タンパク質である請求の範囲第43項のミルク 。 49.該ヒト血清タンパク質が、アルブミン、免疫グロブリン、因子VIII、因子IX 及びプロテインCからなる群より選ばれる請求の範囲第48項のミルク。 50.該血清タンパク質がアルブミンである請求の範囲第49項のミルク。 51.組み換えポリペプチドを含む、トランスジェニックミルクを含む食品処方。 52.該組み換えポリペプチドが該トランスジェニックミルクより少なくとも部分 的に精製されている請求の範囲第51項の食品処方。 53.乳児処方のために適した栄養素が処方された請求の範囲第51項の食品処方。 54.ウシ種のミルク中に組み換えポリペプチドを製造しうるトランスジェニック ウシ種を製造するための方法であって、 請求の範囲第1項のトランスジーンをウシ種の胚標的細胞中に導入し、 それにより形成されたトランスジェニック胚標的細胞又は、それから得られ る胚を、宿主雌ウシ親に移植し、そして 該組み換えポリペプチドをミルク中に製造しうる少なくとも一つの雌の子孫 を同定する ことを含む方法。 55.所望の表現型を有するトランスジェニック非ヒト哺乳動物を製造する方法で あって、 (a) 該トランスジェニックを非ヒト動物の細胞中へ組み込まれたときに該表 現型を与えうるトランスジーンをメチル化し、 (b) 該メチル化されたトランスジーンを該非ヒト哺乳動物の受精卵母細胞中 へ導入して、該受精卵母細胞のゲノムDNA中への該トランスジーンの組み込み を可能とし、 (c) このようにして形成された個々の卵母細胞を着床前胚まで培養し、それ によってそれぞれの該受精卵母細胞のゲノムを複製し、 (d) 該着床前胚のそれぞれから少なくとも一つの細胞を取り出し、そして、 そこに含まれるDNAを遊離させるために該少なくとも一つの細胞を溶解し、 (e) 該遊離されたDNAを、該メチル化されたトランスジーンを切断できる が、該ゲノムDNA中に組み込まれそして該ゲノムDNAが複製された後に、形 成された該トランスジーンのメチル化されていない形を切断できない制限エンド ヌクレアーゼと接触させ、 (f) どの着床前胚が該トランスジーンを組み込んでいるかの指標として、該 着床前胚からのどの細胞が該制限エンドヌクレアーゼによる切断に対して耐性で あるトランスジーンを含むかを検出する ことを含む方法。 56.少なくとも一つの細胞の該取り出しが、該着床前胚のそれぞれのための第1 及び第2の半胚を形成し、そして、該第1の半胚のそれぞれが、工程(d)〜(f )に従って溶解され、分析される請求の範囲第55項の方法: (g) 該第2の半胚の少なくとも一つをクローニングすること、及び (h) 複数のトランスジェニック胚を形成すること。 57.該トランスジェニック胚の1以上を、宿主雌親中に移植して、同じ遺伝子型 を有する少なくとも二つのトランスジェニック非ヒト動物を含む集団を製造する ことを更に含む請求の範囲第56項の方法。 58.ゲノム的に組込まれたトランスジーンを含む該着床前胚の残りを宿主雌親中 に移植し、そして、該表現型を有する少なくとも一つの子孫を同定することを更 に含む請求の範囲第55項の方法。 59.該制限エンドヌクレアーゼがDPNIであり、かつ、該トランスジーンが、 該トランスジーン中に含まれる配列GATCのアデニンのN6においてメチル化 されている、請求の範囲第55項の方法。 60.該検出が、該GATC配列の上流及び下流の配列に対して相補的な伸長プラ イマーを用いるポリメラーゼ連鎖反応を利用する、請求の範囲第59項の方法。 61.該非ヒトトランスジェニック哺乳動物がウシ種であり、該トランスジーンが 組み換えポリペプチドをエンコードしており、そして、該所望の表現型が該ウシ 種のミルク中に該組み換えポリペプチドを製造する能力である、請求の範囲第59 項の方法。 62.該トランスジーンが請求の範囲第3項のトランスジーンである請求の範囲第 61項の方法。 63.(i) ウシ5′発現調節配列、 (ii) ウシ種の乳房分泌細胞中で機能しうる分泌シグナル配列をエンコー ドする分泌DNA配列、 (iii) 組み換えポリペプチドをエンコードする組み換えDNA配列、但し 該分泌DNA配列は、該組み換えDNA配列に操作可能に連結され、ここで分泌 −組み換えDNA配列が形成され、該分泌−組み換えDNA配列は、該ウシ発現 調節配列に操作可能に連結されていること、 (iv) 3′非翻訳配列、 (v) ウシ遺伝子の3′フランキング配列、 を含む、トランスジェニックウシ種のミルク中に組み換え ポリペプチドを製造するためのトランスジーンであって、 該トランスジーンが、該トランスジーンを含むウシ種の乳房分泌細胞中に該分 泌−組み換えDNA配列の発現を引き起こすことができて、該乳房分泌細胞から 分泌されたときに該ウシ種のミルク中に組み換えポリペプチドを製造する組み換 えポリペプチドの形を製造するところのトランスジーン。 64.更に組み換え介在配列を含む請求の範囲第63項のトランスジーン。 65.組み換え介在配列がハイブリッド介在配列である請求の範囲第64項のトラン スジーン。 66.ハイブリッド介在配列が、ウシαS1−カゼインからの介在配列の5′部分 及びIgG重鎖介在配列の3′配列部分を含む、請求の範囲第65項のトランスジ ーン。 67.3′配列部分が、IgG重鎖のJ−Cセグメント再配列と関連した3′スプ ライスシグナル配列である請求の範囲第66項のトランスジーン。 68.ウシ発現調節配列及び3′フランキング配列が同じウシ遺伝子由来である請 求の範囲第63項のトランスジーン。 69.ウシ発現調節配列、3′非翻訳配列及び3′フランキング配列が同じウシ遺 伝子由来である請求の範囲第63項のトランスジーン。 70.ウシ遺伝子がαS1−カゼインである請求の範囲第68項又は第69項のトラン スジーン。 71.ウシ発現調節配列がウシαS1−カゼインの約30kbの 5′フランキング領域を含み、3′フランキング配列がウシαS1−カゼインの 約15kbの3′フランキング領域を含む、請求の範囲第70項のトランスジーン。 72.ミルクが、ミリリットル当たり50マイクログラムより多い組み換えポリペプ チドを含む請求の範囲第3項又は第63項のトランスジーン。 73.唾液中に組み換えポリペプチドを製造できるトランスジェニックウシ種。 74.トランスジェニックウシの精液。 75.(i) 5′発現調節配列、 (ii) ウシ種の乳房分泌細胞中で機能できる分泌シグナル配列をエンコー ドする分泌DNA配列、 (iii) 組み換えポリペプチドをエンコードする組み換えDNA配列、但し 該分泌DNA配列は、該組み換えDNA配列に操作可能に連結され、ここで分泌 −組み換えDNA配列が形成され、該分泌−組み換えDNA配列は、5′発現調 節配列に操作可能に連結されていること、 (iv) 3′非翻訳配列、及び (v) ヒト遺伝子からの3′フランキング配列、 を含む、トランスジェニックウシ種のミルク中に組み換えポリペプチドを製造す るためのトランスジーンであって、 該トランスジーンが該トランスジーンを含むウシ種の乳房分泌細胞中に分泌− 組み換えDNA配列の発現を引き起こすことができて、乳房分泌細胞から分泌さ れたときにウシ種のミルク中に組み換えポリペプチドを製造する組み換 えポリペプチドの形を製造するところのトランスジーン。 76.5′発現調節配列がウシ配列である請求の範囲第75項のトランスジーン。 77.3′フランキング配列がヒトラクトフェリン(hLF)遺伝子由来である請 求の範囲第75項又は第76項のトランスジーン。 78.3′フランキング配列が長さが9キロベースペアである、請求の範囲第77項 のトランスジーン。 79.組み換えポリペプチドがヒトラクトフェリンである請求の範囲第77項のトラ ンスジーン。 80.5′発現調節配列、分泌DNA配列、組み換えポリペプチドをエンコードす る組み換えDNA配列、3′非翻訳配列及び3′フランキング配列がヒト遺伝子 由来である請求の範囲第75項のトランスジーン。 81.ヒト遺伝子がラクトフェリン遺伝子である請求の範囲第80項のトランスジー ン。 82. ヒトポリペプチドをエンコードするヒトゲノムフラグメントをウシ種の 胚標的細胞中に導入し、 それにより形成されたトランスジェニック胚標的細胞又は、それから得られ た胚を宿主雌ウシ親中に移植し、そして 組み換えポリペプチドをミルク中に製造しうる少なくとも一つの雌の子孫を 同定する ことを含む、ウシのミルク中にヒトポリペプチドを発現する方法。 83.ヒトポリペプチドがラクトフェリンである請求の範囲第82項の方法。
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US89895692A | 1992-06-15 | 1992-06-15 | |
US07/898,956 | 1992-06-15 | ||
PCT/US1993/005724 WO1993025567A1 (en) | 1992-06-15 | 1993-06-15 | Production of recombinant polypeptides by bovine species and transgenic methods |
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EP (1) | EP0652889A4 (ja) |
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Cited By (4)
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JP2002017357A (ja) * | 2000-07-04 | 2002-01-22 | Calpis Co Ltd | アンカーペプチド、融合蛋白質、及び蛋白質の固定化方法 |
JP2002531581A (ja) * | 1998-12-07 | 2002-09-24 | ファーミング インテレクチュアル プロパティー ベー.フェー. | ポンペ病の処置 |
JP2004537980A (ja) * | 2001-04-03 | 2004-12-24 | ソシエテ デ プロデユイ ネツスル ソシエテ アノニム | 乳中の破骨細胞分化抑制因子 |
JP2010539946A (ja) * | 2007-09-26 | 2010-12-24 | イントレキソン コーポレーション | 合成5’utr、発現ベクター、および導入遺伝子の発現を増加させる方法 |
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US5856178A (en) * | 1993-08-30 | 1999-01-05 | Utah State University | DNA cassettes for expression of lytic peptides in mammalian cells and transgenic organisms containing same |
WO1995018224A1 (en) * | 1993-12-29 | 1995-07-06 | Gene Pharming Europe Bv | Recombinant production of modified proteins lacking certain amino acids |
WO1995024488A1 (en) * | 1994-03-09 | 1995-09-14 | Abbott Laboratories | Transgenic animals producing oligosaccharides and glycoconjugates |
US5627268A (en) * | 1994-06-07 | 1997-05-06 | Dnx Biotherapeutics | Hemoglobin comprising globin fusion proteins |
JPH10502816A (ja) * | 1994-07-13 | 1998-03-17 | ピーピーエル・セラピューティクス(スコットランド)リミテッド | α−ラクトアルブミン遺伝子構造物 |
GB9425326D0 (en) * | 1994-12-15 | 1995-02-15 | Ppl Therapeutics Scotland Ltd | Gene constructs |
US5780009A (en) * | 1995-01-20 | 1998-07-14 | Nexia Biotechnologies, Inc. | Direct gene transfer into the ruminant mammary gland |
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US6118045A (en) * | 1995-08-02 | 2000-09-12 | Pharming B.V. | Lysosomal proteins produced in the milk of transgenic animals |
EP1262191A1 (en) * | 1995-08-02 | 2002-12-04 | Pharming B.V. | Pharmaceutical compositions comprising recombinant human acid alpha-glucosidase containing mannose 6-phosphate |
US5907080A (en) * | 1995-11-30 | 1999-05-25 | Nexia Biotechnologies, Inc. | Method for development of transgenic dwarf goats |
US6077697A (en) | 1996-04-10 | 2000-06-20 | Chromos Molecular Systems, Inc. | Artificial chromosomes, uses thereof and methods for preparing artificial chromosomes |
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US7417178B2 (en) | 2000-05-02 | 2008-08-26 | Ventria Bioscience | Expression of human milk proteins in transgenic plants |
US20040088744A1 (en) * | 2000-08-14 | 2004-05-06 | Alan Attie | Fatty liver disease resistant bovines |
US8409861B2 (en) | 2003-08-08 | 2013-04-02 | Sangamo Biosciences, Inc. | Targeted deletion of cellular DNA sequences |
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JP2874751B2 (ja) * | 1986-04-09 | 1999-03-24 | ジェンザイム・コーポレーション | 希望する蛋白質をミルク中へ分泌する遺伝子移植動物 |
AU7879987A (en) * | 1986-08-28 | 1988-03-24 | Immunex Corp. | Expression of heterologous proteins by transgenic lactating mammals |
US4873316A (en) * | 1987-06-23 | 1989-10-10 | Biogen, Inc. | Isolation of exogenous recombinant proteins from the milk of transgenic mammals |
CA2351200A1 (en) * | 1989-12-01 | 1991-06-13 | Gene Pharming Europe Bv | Production of recombinant polypeptides by bovine species and transgenic methods |
JPH04365487A (ja) * | 1990-04-11 | 1992-12-17 | Consortium Elektrochem Ind Gmbh | 組換dna−構造体、組換ベクター、トランスゲン動物の乳からの蛋白質の取得法、トランスゲン動物の製法及びトランスゲン動物の乳 |
DK8892D0 (da) * | 1992-01-23 | 1992-01-23 | Symbicom Ab | Humant proteingen |
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1993
- 1993-06-15 WO PCT/US1993/005724 patent/WO1993025567A1/en not_active Application Discontinuation
- 1993-06-15 EP EP93915365A patent/EP0652889A4/en not_active Withdrawn
- 1993-06-15 JP JP50179494A patent/JP3670003B2/ja not_active Expired - Fee Related
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Cited By (4)
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JP2002531581A (ja) * | 1998-12-07 | 2002-09-24 | ファーミング インテレクチュアル プロパティー ベー.フェー. | ポンペ病の処置 |
JP2002017357A (ja) * | 2000-07-04 | 2002-01-22 | Calpis Co Ltd | アンカーペプチド、融合蛋白質、及び蛋白質の固定化方法 |
JP2004537980A (ja) * | 2001-04-03 | 2004-12-24 | ソシエテ デ プロデユイ ネツスル ソシエテ アノニム | 乳中の破骨細胞分化抑制因子 |
JP2010539946A (ja) * | 2007-09-26 | 2010-12-24 | イントレキソン コーポレーション | 合成5’utr、発現ベクター、および導入遺伝子の発現を増加させる方法 |
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AU4537393A (en) | 1994-01-04 |
EP0652889A4 (en) | 1997-05-07 |
WO1993025567A1 (en) | 1993-12-23 |
JP3670003B2 (ja) | 2005-07-13 |
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