JP2006122059A - Swedish変異を有するAPP対立遺伝子を含有するトランスジェニック動物 - Google Patents
Swedish変異を有するAPP対立遺伝子を含有するトランスジェニック動物 Download PDFInfo
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Abstract
【解決手段】ヒトAPP695中の595 位と596 位に相当する位置のアミノ酸残基がそれぞれアスパラギンとロイシンであるSwedish 変異を含む非相同APP ポリペプチドをコードするトランスジーンを含んで成る二倍体ゲノムを有するトランスジェニック非ヒト動物において、前記トランスジーンが発現されてSwedish変異を有するヒトAPPポリペプチドが生産され、当該ポリペプチドが、トランスジェニック齧歯動物の脳ホモジネート中で、APPと反応することなくATP−βAPPと反応する抗体を用いることにより検出される量でATF−βAPPにプロセッシングされる、ことを特徴とするトランスジェニック齧歯動物。
【選択図】なし
Description
アルツハイマー病は、AD患者の脳、特に記憶と認識に関係する領域中にみられる多数のアミロイド斑と神経原繊維のもつれ(非常に不溶性のタンパク質凝集物)の存在により特徴付けられる。
本発明はまた、少なくとも1つの不活性化された内因性APP対立遺伝子を有し、そして好ましくは不活性化されたAPP対立遺伝子に対して同型接合であり、且つ内因性(即ち野性型)APPの効率的発現を指令することが実質的にできない、トランスジェニック非ヒト動物、例えば非霊長類哺乳動物も提供する。
異なって定義されない限り、本明細書中で使われる全ての技術用語と科学用語は、本発明が属する当業界の普通の技術者により一般に理解されるのと同じ意味を有する。本明細書中に記載されるのと類似しているがまたは同等であるいずれの方法および材料も本発明の実施または試験に使うことができるが、好ましい方法および材料が記載される。本発明の目的上、次の用語を下記に定義する。
本明細書中で使用する「同族(cognate)」という用語は、種間で進化論的におよび機能的に関連している遺伝子配列を指して言う。非限定的な例として、ヒトゲノムでは、ヒト免疫グロブリン重鎖遺伝子座はマウス免疫グロブリン重鎖遺伝子座と同族の遺伝子である。何故なら、それら2つの遺伝子の配列と構造は、両者が高度に相同性であり且つ両遺伝子とも特異的に抗原を結合する働きをするタンパク質をコードするからである。
本明細書中で使用する時、「連結された」とは、ポリヌクレオチド結合(即ち、ホスホジエステル結合)になっていることを意味する。「未連結の」とは、他のポリヌクレオチド配列に連結されていないことを意味する。よって、各々の配列が遊離の5′末端と遊離の3′末端を有するならば、2つの配列は未連結である。
本明細書中で使用する時、「コドン595」および「コドン596」は、APP695中の595 および596 番目のアミノ酸位置、またはKang他(1987)前掲における番号付け法に従ったAPP695中の595 および596 番目の位置に相当するAPPイソ型タンパク質もしくは断片中のアミノ酸位置、をコードするコドンのことを言う。
一般的に、下記で使用する命名法と、後述する細胞培養、分子遺伝学並びに核酸化学およびハイブリダイゼーションにおける実験手順は、当業界で公知であり且つ常用されるものである。組換え核酸法、ポリヌクレオチド合成、細胞培養、およびトランスジェン導入(例えばエレクトロポレーション、マイクロインジェクション、リポフェクション)には標準技術が使われる。酵素反応、オリゴヌクレオチド合成および精製段階は一般に製造業者の説明書に従って実施される。方法および手順は一般に当業界での常法および本明細書中に与えられる様々な参考文献に従って実施される。その中の手順は当業界で周知であると思われるが、読者の便宜のために与えられる。その中に含まれる情報は全て参考として本明細書中に組み込まれる。
胎児性幹細胞は発表された手順〔Teratocarcinomas and Embryo-nic Stem Cells: A Practical Approach, E.J. Robertson編, IRLPress, Washington, D.C., (1987) ;Zjilstra他、Nature 342:435-438 (1989);およびSchwartzberg他、Science 246: 799-803(1989)、その各々は参考として本明細書中に組み込まれる〕に従って操作される。
オリゴヌクレオチドは、製造業者により与えられた指針に従ってApplied Bio Systems オリゴヌクレオチド合成装置上で合成することができる。
本発明の好ましい態様では、Swedish 変異を含むAPPポリペプチドを発現するトランスジェニック非ヒト動物を製造するために、Swedish 変異(アスパラギン595−ロイシン596)を含む非相同APPタンパク質をコードするトランスジェンが受精胚またはES細胞中に移入される。非相同Swedish 変異APPタンパク質をコードするトランスジェンは、非相同Swedish 変異APPタンパク質をコードする構造配列を含み、そして通常は更に非ヒト宿主中での非相同Swedish 変異APPタンパク質の発現を指令する連結された調節要素も含んで成る。しかしながら、非相同構造配列の発現に適当である機能的な内因性調節要素を含む染色体部位にトランスジェン配列を組み込むことにより、非ヒト宿主のゲノム中の内因性調節要素を活用してもよい。そのような標的組み込みは、普通は上述したような相同遺伝子ターゲティングによって行われる。この場合、前記非相同トランスジェンは少なくとも1つの相同性クランプを含んで成るだろう。
ある態様では、Swedish 変異を含むトランスジェンによりコードされるAPPを妨害または汚染しないように内因性的にコードされるAPPの発現が抑制または排除されるように、内因性非ヒトAPP対立遺伝子が機能的に破壊される。1つの変形として、内因性APP対立遺伝子が、相同遺伝子ターゲティングによりSwedish 変異を含むように変換される。
本発明は、相同組換えターゲティング構成物を使った遺伝子ターゲティングにより不活性化された内因性APP遺伝子を有する非ヒト動物(例えば非霊長類哺乳動物)を作製するための方法を包含する。典型的には、ターゲティング構成物中の相同性クランプとして使われるであろう領域に隣接するPCRプライマーを製造するための基礎として非ヒトAPP遺伝子配列が使われる。
ターゲティング構成物が内因性APP遺伝子座の一部と相同的に組み換わり、内因性APP遺伝子の機能的発現を妨げる1または複数の変異(即ち挿入、欠失、再配列、配列置換、および/または点変異)を造成するような多分化能性幹細胞(例えばマウス胎児性幹細胞)にターゲティング構成物を導入することができる。
本発明の別の好ましい方法は、ポリヌクレオチド配列の標的挿入により内因性APP遺伝子の必須構造要素および/または調節要素を中断し、それによって内因性APP遺伝子を機能的に破壊することである。
本発明の一態様では、非ヒト宿主中の内因性APP遺伝子が、Swedish 変異を含む同族の非相同APP遺伝子セグメントを含まないターゲティング構成物を使った相同組換えにより機能的に破壊される。この態様では、ターゲティング構成物の一部分が内因性APP遺伝子座の必須構造要素または調節要素中に組み込まれ、それによって該遺伝子座を機能的に破壊してヌル対立遺伝子を生ぜしめる。典型的には、ターゲティング構成物の相同性クランプと内因性APP遺伝子配列との相同組換えにより、APP遺伝子の必須構造および/または調節配列中に選択可能マーカー(例えばneo 遺伝子発現カセット)をコードする非相同配列を組み込むことにより、ヌル対立遺伝子が作製されるが、他の方策(下記参照)を使用してもよい。
本発明の別の変形によれば、同族非相同APP遺伝子が、少なくともKangら(1987)前掲の番号付け法に従ったアミノ酸位置595-596に及ぶ内因性APP遺伝子を実質的に置換し、好ましくは内因性APP遺伝子のコード配列を完全に置換するように、Swedish 変異を含む同族非相同APP遺伝子の相同組込みにより非ヒト宿主中の内因性APP遺伝子が機能的に破壊される。好ましくは相同組込みの結果として、非相同Swedish 変異遺伝子が内因性APP遺伝子座からの調節要素の転写調節下で発現されるように、非相同Swedish 変異遺伝子が内因性APP遺伝子の調節配列(例えばエンハンサー)に連結される。そのような置換対立遺伝子に対して同型接合である非ヒト宿主(即ち、同族非相同Swedish 変異APP遺伝子産物をコードする宿主染色体APP遺伝子座)は本明細書中に記載の方法に従って作製することができる。
幾つかの遺伝子ターゲティング技術が記載されており、その非限定的例としては、同時エレクトロポレーション、「ヒット・アンド・ラン」、一重交差組込み、および二重交差組換えが挙げられる〔Bradley 他 (1992) Bio/Technology 10:534〕。本発明は、本質的には任意の当業界で公知の適用可能な相同遺伝子ターゲティング方法を使って実施することができる。ターゲティング構成物の配置は選択される特定のターゲティング技術に依存する。例えば、一重交差組込みまたは「ヒット・アンド・ラン」ターゲティングのためのターゲティング構成物は、ターゲティング領域に連結された単一の相同性クランプのみを必要とし、一方で二重交差置換型ターゲティング構成物は、置換領域の各側に隣接する2つの相同性領域を必要とする。
Swedish 変異APP(従ってSwedish 変異Aβ)をコードするトランスジェンを含んで成る非ヒト動物は、Aβの生産および/または蓄積を低下させる効果を有する剤についてスクリーニングするために商業的に利用することができる。そのような剤は、異常なAPPプロセシングおよび/または数ある神経変性状態の中でも特にアルツハイマー病を治療するための薬として開発することができる。例えば、Donehower 他 (1992) Nature 356: 215の p53ノックアウト(破壊)マウスは、発癌物質スクリーニング用等の商品として広く受け入れられている。
Swedish 変異を含むAPPポリペプチドを使って、例えばKohlerおよびMilsteinの方法〔 (1975) Nature 256: 495〕により、抗血清とモノクローナル抗体を調製することが可能である。次いで、そのような抗体は特にSwedish 変異の存在についての診断試験の基礎を形作ることができる。
実験例
抗体 6C6はβAPの残基1〜16内のエピトープを認識する。
Swedish 変異APPを発現するトランスジェニックマウス
図1に示されるプラスミド(NSEAPPswとNSEAPPswΔ3')を使ってトランスジェニックマウスを作製した。それらのプラスミドは、Swedish 変異を含むβAPPの751 形(695 形の595 位と596 位がKMからNLに変異)を含有する。
免疫原としてウサギ血清アルブミンに接合されたβAP残基1〜28を含有する合成ペプチドを使って、モノクローナル抗体 6C6を惹起せしめそして抗体10D5〔Hyman 他 (1992) J. Neuropath. Exp. Neurol. 51: 76〕と同じ方法でスクリーニングした。10D5も6C6も両方ともβAP配列の最初の16アミノ酸中のエピトープを認識する。6C6 は免疫沈澱において10D5よりも効果的であり、従って捕捉抗体として使用した。
該接合体を出発のcBSAと6% Novex充填済Tris−グリシンゲル上で比較した。好結果の接合は、目に見える高分子量へのシフトにより示される。
当業者に明らかであろうそのような修正や変更は本発明の範囲内にある。
本明細書中に言及される全ての刊行物および特許出願は、あたかも個々の刊行物または特許出願が具体的に且つ個別的に参考として組み込まれると指摘されたかのように、参考として本明細書中に組み込まれる。
Claims (7)
- ヒトAPP695中の595 位と596 位に相当する位置のアミノ酸残基がそれぞれアスパラギンとロイシンであるSwedish 変異を含む非相同APP ポリペプチドをコードするトランスジーンを含んで成る二倍体ゲノムを有するトランスジェニック非ヒト動物において、前記トランスジーンが発現されてSwedish変異を有するヒトAPPポリペプチドが生産され、当該ポリペプチドが、トランスジェニック齧歯動物の脳ホモジネート中で、APPと反応することなくATP−βAPPと反応する抗体を用いることにより検出される量でATF−βAPPにプロセッシングされる、ことを特徴とするトランスジェニック齧歯動物。
- 前記動物がマウスである、請求項1のトランスジェニック齧歯動物。
- 前記トランスジェニック齧歯動物がSwedish 変異を含むヒトAPP ポリペプチドを発現する、請求項1のトランスジェニック齧歯動物。
- 前記Swedish 変異を含む非相同APP ポリペプチドが、神経特異的エノラーゼプロモーターの転写調節下で発現される、請求項1のトランスジェニック齧歯動物。
- アミロイド前駆体タンパク質のβ−アミロイドペプチドへのプロセシングに影響を及ぼす事が出来る物質をスクリーニングする方法において、
ヒトAPP695における位置595及び596に対応する位置のアミノ酸残基がそれぞれアスパラギン及びロイシンであるSwedish変異を有するヒトAPPポリペプチドをコードするトランスジーンを含んで成る二倍体ゲノムを有するトランスジェニック齧歯動物を用意し、ここで、前記トランスジーンは発現されて前記Swedish変異を有するヒトAPPポリペプチドを産生するものであり、そして前記ポリペプチドは、前記トランスジェニック齧歯動物の脳ホモジネート中で、APPと反応することなくATP−βAPPと反応する抗体を用いることにより検出される量でATF−βAPPにプロセッシングされ、
前記トランスジェニック齧歯動物を物質と接触せしめ、そして
前記物質が開裂に影響を及ぼすのを示すために、前記接触されたトランスジェニック齧歯動物における、β−アミロイドペプチドのN−末端とATF−βAPPとの間での前記アミロイド前駆体タンパク質の開裂を、対照トランスジェニック齧歯動物での開裂と比較してモニターする、
ことを含んで成る方法。 - 前記物質が、前記開裂と関連するβ−セクレターゼ活性を阻害する、請求項5に記載の方法。
- 前記トランスジェニック齧歯動物を、1ng/kg〜10 mg/kgの量で前記物質と接触せしめる、請求項5に記載の方法。
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US08/143,697 US5604102A (en) | 1992-04-15 | 1993-10-27 | Methods of screening for β-amyloid peptide production inhibitors |
US08/148,211 US5612486A (en) | 1993-10-27 | 1993-11-01 | Transgenic animals harboring APP allele having swedish mutation |
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PT730643E (pt) * | 1993-10-27 | 2001-06-29 | Lilly Co Eli | Animais transgenicos portadores do alelo de app com mutacao sueca |
CA2182311A1 (en) | 1994-01-27 | 1995-08-03 | Karen Hsiao | Transgenic non-human mammals with progressive neurologic disease |
US5877399A (en) | 1994-01-27 | 1999-03-02 | Johns Hopkins University | Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease |
US5777194A (en) * | 1995-04-26 | 1998-07-07 | Cephalon, Inc. | Gene-targeted mice with humanized Aβ sequence and Swedish FAD mutation |
EP0833901A1 (en) * | 1995-06-07 | 1998-04-08 | Athena Neurosciences, Inc. | Method for identifying alzheimer's disease therapeutics using transgenic animal models |
AU6264996A (en) * | 1995-06-07 | 1996-12-30 | Athena Neurosciences, Inc. | Method for identifying alzheimer's disease therapeutics usin g transgenic animal models |
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- 1994-10-18 EP EP99204266A patent/EP1001019A1/en not_active Withdrawn
- 1994-10-18 DE DE1001019T patent/DE1001019T1/de active Pending
- 1994-10-18 DE DE69426571T patent/DE69426571T2/de not_active Expired - Lifetime
- 1994-10-18 DK DK94931891T patent/DK0730643T3/da active
- 1994-10-18 CA CA2174429A patent/CA2174429C/en not_active Expired - Lifetime
- 1994-10-18 AU AU80809/94A patent/AU702293B2/en not_active Expired
- 1994-10-18 WO PCT/US1994/011827 patent/WO1995011968A1/en active IP Right Grant
- 1994-10-18 JP JP7512698A patent/JPH09507746A/ja not_active Withdrawn
-
1997
- 1997-01-22 US US08/785,943 patent/US5850003A/en not_active Expired - Lifetime
-
1998
- 1998-12-10 US US09/209,647 patent/US6245964B1/en not_active Expired - Fee Related
-
2001
- 2001-03-13 GR GR20010400410T patent/GR3035564T3/el unknown
- 2001-04-18 US US09/838,556 patent/US6586656B2/en not_active Expired - Fee Related
-
2003
- 2003-06-27 US US10/609,143 patent/US7179953B2/en not_active Expired - Fee Related
-
2006
- 2006-01-23 JP JP2006014221A patent/JP2006122059A/ja active Pending
- 2006-12-20 US US11/643,717 patent/US7608749B2/en not_active Expired - Fee Related
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2007
- 2007-05-16 JP JP2007130911A patent/JP2007267748A/ja not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
DE69426571D1 (de) | 2001-02-15 |
US7179953B2 (en) | 2007-02-20 |
EP0730643A4 (en) | 1996-11-27 |
AU702293B2 (en) | 1999-02-18 |
US7608749B2 (en) | 2009-10-27 |
WO1995011968A1 (en) | 1995-05-04 |
JPH09507746A (ja) | 1997-08-12 |
PT730643E (pt) | 2001-06-29 |
JP2007267748A (ja) | 2007-10-18 |
US20020049988A1 (en) | 2002-04-25 |
DE69426571T2 (de) | 2001-08-09 |
GR3035564T3 (en) | 2001-06-29 |
AU8080994A (en) | 1995-05-22 |
ATE198622T1 (de) | 2001-01-15 |
DE1001019T1 (de) | 2001-01-11 |
CA2174429A1 (en) | 1995-05-04 |
ES2155099T3 (es) | 2001-05-01 |
EP0730643B1 (en) | 2001-01-10 |
US20050022257A1 (en) | 2005-01-27 |
DK0730643T3 (da) | 2001-05-14 |
US5850003A (en) | 1998-12-15 |
US6245964B1 (en) | 2001-06-12 |
EP1001019A1 (en) | 2000-05-17 |
EP0730643A1 (en) | 1996-09-11 |
US6586656B2 (en) | 2003-07-01 |
CA2174429C (en) | 2011-08-30 |
US20070199079A1 (en) | 2007-08-23 |
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