JP2015523863A - ヒト化il−7齧歯類 - Google Patents
ヒト化il−7齧歯類 Download PDFInfo
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- JP2015523863A JP2015523863A JP2015517447A JP2015517447A JP2015523863A JP 2015523863 A JP2015523863 A JP 2015523863A JP 2015517447 A JP2015517447 A JP 2015517447A JP 2015517447 A JP2015517447 A JP 2015517447A JP 2015523863 A JP2015523863 A JP 2015523863A
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Abstract
Description
非ヒトIL−7遺伝子配列の内因性遺伝子座において、ヒトIL−7遺伝子配列での置換を含む遺伝子改変を含む、非ヒト動物(例えば、哺乳動物、例えば、マウス、ラット、およびハムスターのような齧歯類)。内因性非ヒト調節配列の制御下にある遺伝子座から、または内因性非ヒト調節配列を含む内因性非ヒトIL−7遺伝子座から、ヒトIL−7もしくはヒト化IL−7を発現する齧歯類および他の非ヒト動物。
ヒトIL−7配列を含む無作為に挿入された導入遺伝子を有するトランスジェニックマウスは、当該分野で公知である。しかし、これらトランスジェニックマウスのうちの全てではないにしても大部分は、どのような局面にせよ最適ではない。例えば、ヒトIL−7に対してトランスジェニックの大部分のマウスは、免疫細胞発生(例えば、T細胞発生)の調節異常(dysregulation)におそらく起因する、特定の細胞(T細胞が挙げられる)の異常なレベルおよび/もしくは比を示す。
遺伝子改変された非ヒト動物、細胞、組織、および核酸が提供され、これらは、内因性非ヒトIL−7遺伝子座においてヒトIL−7ゲノム配列を含む。上記非ヒト動物は、改変された内因性IL−7遺伝子座の1もしくは複数の内因性非ヒト調節配列によって調節される改変された遺伝子座からヒト化IL−7タンパク質を発現する。種々の実施形態において、上記非ヒト動物は、齧歯類、例えば、マウス、ラット、ハムスターなどである。具体的実施形態において、上記齧歯類は、マウスもしくはラットである。
種々の実施形態において、本明細書で記載される遺伝子改変を含む非ヒト動物が、記載される。上記遺伝子改変された非ヒト動物は、マウス、ラット、ウサギ、ブタ、ウシ(例えば、雌牛、雄牛、水牛)、シカ、ヒツジ、ヤギ、ニワトリ、ネコ、イヌ、フェレット、霊長類(例えば、マーモセット、アカゲザル)からなる群より選択され得る。適切な遺伝子改変可能なES細胞が、容易に入手できない非ヒト動物に関しては、遺伝子改変を含む非ヒト動物を作製するために、他の方法が使用される。このような方法としては、例えば、非ES細胞ゲノム(例えば、線維芽細胞もしくは人工多能性細胞)を改変すること、および改変されたゲノムを適切な細胞(例えば、卵母細胞)に移入するために核移植を使用すること、および上記改変された細胞(例えば、改変された卵母細胞)を適切な条件下で非ヒト動物の中で懐胎させて、胚を形成することが挙げられる。
マウスES細胞を、内因性マウスIL−7遺伝子座において、マウスIL−7調節エレメントの制御下で、VELOCIGENE(登録商標)遺伝子工学技術を使用して、マウスIL−7遺伝子配列をヒトIL−7遺伝子配列で置換するように改変して、図1に示されるとおりのヒト化遺伝子座を産生した。
ヒト化IL−7マウスの生成。 ヒト化IL−7遺伝子座を含むドナーマウスES細胞を、VELOCIMOUSE(登録商標)法(Poueymirou et al. (2007) F0 generation mice fully derived from gene−targeted embronic stem cells allowing immediate phenotypic analyses, Nat Biotechnol 25:91−99)によって、初期段階のマウス胚に導入する。ドナーES細胞に完全に由来する4個のF0マウスを得た。これは、内因性マウスIL−7遺伝子座のヒト化に関してヘテロ接合性であった。F0マウスを、上記ヒト化に関してホモ接合性になるように交配する。ホモ接合性マウスを、ホモ接合性を確認するために遺伝子型決定する。全てのマウス研究は、Regeneron’s Institutional Animal Care and Use Committee(IACUC)が監督および承認した。
上記IL−7遺伝子に関してヒト化したマウスおよびそれらの非ヒト化同腹仔コントロールから採血し、ヒトIL−7の血清濃度を、QuantikineHS Human IL−7 Immunoassayキット(R&D Systems, Inc製)を使用して測定した。Microsoft Excelを使用してデータを分析し、Prism統計分析ソフトウェアを使用してプロットした。上記ヒト化IL−7遺伝子座に関してヘテロ接合性のマウス(MAID 5148 hetと称した)は、生理学的に関連する濃度で血清中にヒトIL−7を発現した。これは、二重ノックアウトマウスにおいてレンチウイルスで形質導入したヒトIL−7を有するトランスジェニックヒトIL−7マウスとは対照的である。このマウスは、非生理学的でかつ潜在的に非常に有害な高レベルの血清中のヒトIL−7(10〜100pg/mL)を示す(O’Connell, R.M. et al. (2010) Lentiviral Vector Delivery of Human Interleukin−7 (hIL−7) to Human Immune System (HIS) Mice Expands T Lymphocyte Populations, PLoS ONE 5(8):e12009)。対照的に、ヒト化内因性IL−7遺伝子座に関してヘテロ接合性のマウスは、血清中約2.4〜約3.2pg/mLを示した(図2)。これは、IL−7の正常なもしくは生理学的に適切なレベルを示す。
Claims (30)
- ヒトもしくはヒト化IL−7コード遺伝子を形成するために少なくとも1つの非ヒトIL−7エキソンの少なくとも1つのヒトIL−7エキソンでの置換を生殖細胞系列に含む、遺伝子改変された非ヒト動物であって、ここで該置換は、内因性非ヒトIL−7遺伝子座にあり、該ヒトもしくはヒト化IL−7コード遺伝子は、内因性非ヒト調節エレメントの制御下にある、遺伝子改変された非ヒト動物。
- 齧歯類である、請求項1に記載の遺伝子改変された非ヒト動物。
- 前記齧歯類は、ラットおよびマウスから選択される、請求項2に記載の遺伝子改変された齧歯類。
- 前記ヒトもしくはヒト化IL−7コード遺伝子は、ヒトエキソン1、ヒトエキソン2、ヒトエキソン3、ヒトエキソン4、ヒトエキソン5、ヒトエキソン6、およびこれらの組み合わせからなる群より選択されるヒトエキソンを含む、請求項2に記載の遺伝子改変された齧歯類。
- 前記ヒトもしくはヒト化IL−7コード遺伝子は、5つ以下のヒトエキソンを含む、請求項4に記載の遺伝子改変された齧歯類。
- 前記齧歯類は、マウスであり、前記改変された遺伝子座は、マウスエキソン2、3、4、および5の、ヒトIL−7エキソン2、3、4、5、および6を含むヒトゲノムセグメントでの置換を含む、請求項3に記載の遺伝子改変された齧歯類。
- 前記ヒトもしくはヒト化IL−7コード遺伝子は、ヒトもしくはヒト化IL−7タンパク質をコードするcDNAを含む、請求項1に記載の遺伝子改変された非ヒト動物。
- 生殖細胞系列に、ヒトもしくはヒト化IL−7遺伝子をコードする核酸配列を含む導入遺伝子を含む、遺伝子改変された非ヒト動物であって、ここで該ヒトもしくはヒト化IL−7遺伝子は、内因性非ヒト調節配列と上流および下流に隣接している、遺伝子改変された非ヒト動物。
- 齧歯類である、請求項8に記載の遺伝子改変された非ヒト動物。
- マウス、ラット、およびハムスターからなる群より選択される、請求項9に記載の齧歯類。
- 前記ヒトもしくはヒト化IL−7遺伝子は、ヒトエキソン1、ヒトエキソン2、ヒトエキソン3、ヒトエキソン4、ヒトエキソン5、ヒトエキソン6、およびこれらの組み合わせからなる群より選択されるヒトエキソンを含む、請求項8に記載の遺伝子改変された非ヒト動物。
- 前記ヒトもしくはヒト化IL−7遺伝子は、少なくとも5つのヒトエキソンを含む、請求項11に記載の遺伝子改変された非ヒト動物。
- ヒトもしくはヒト化IL−7コード遺伝子を有する非ヒト動物を作製するための方法であって、該方法は、該非ヒト動物の生殖細胞系列を、内因性非ヒトIL−7調節配列と上流および下流に隣接したヒトもしくはヒト化IL−7コード遺伝子を含むように改変する工程を包含する、方法。
- 前記改変は、内因性非ヒトIL−7遺伝子座にある、請求項13に記載の方法。
- 前記非ヒト動物は齧歯類である、請求項13に記載の方法。
- 前記齧歯類は、マウス、ラット、およびハムスターからなる群より選択される、請求項15に記載の方法。
- 同じ属もしくは種の野生型非ヒト動物に関して観察されるものと同じ発現パターンである発現パターンで、ヒトIL−7を発現するように遺伝子改変されている、遺伝子改変された非ヒト動物。
- 前記非ヒト動物において発現されるヒトIL−7のレベルは、対応する野生型マウスにおける非ヒトIL−7のレベルとほぼ同じである、請求項17に記載の遺伝子改変された非ヒト動物。
- 齧歯類である、請求項17に記載の遺伝子改変された非ヒト動物。
- 齧歯類である、請求項18に記載の遺伝子改変された非ヒト動物。
- 非ヒトIL−7エキソン1、ヒトIL−7エキソン2、ヒトIL−7エキソン3、ヒトIL−7エキソン4、ヒトIL−7エキソン5およびヒトIL−7エキソン6を含む、ヒト化IL−7遺伝子座。
- 前記ヒト化IL−7遺伝子座は、前記非ヒトIL−7エキソン1およびヒトIL−7エキソン6に隣接する5’および3’非ヒトIL−7非翻訳領域をさらに含む、請求項21に記載のヒト化IL−7遺伝子座。
- 前記ヒト化IL−7遺伝子座は、非ヒト3’非翻訳領域と連続する、3’ヒト非翻訳領域もしくはその一部を含む、請求項21もしくは22に記載のヒト化IL−7遺伝子座。
- 前記ヒト化IL−7遺伝子座は、5’非ヒトIL−7非翻訳領域、またはその一部を含み、非ヒトIL−7エキソン1は、ヒトIL−7エキソン2と連続している、請求項21〜23のいずれか1項に記載のヒト化IL−7遺伝子座。
- 前記ヒト化IL−7遺伝子座は、図1に示される構造を含む、請求項21〜24のいずれか1項に記載のヒト化IL−7遺伝子座。
- 請求項21〜25のいずれか1項に記載のヒト化IL−7遺伝子座を含む、細胞。
- 前記細胞は、胚性幹細胞である、請求項26に記載の細胞。
- 請求項1〜12および17〜20のいずれか1項に記載の非ヒト動物から単離された、細胞もしくは組織。
- 前記組織は、胸腺組織、脾臓組織、表皮組織、および腸組織からなる群より選択される、請求項28に記載の細胞もしくは組織。
- 前記組織は、胸腺組織である、請求項29に記載の細胞もしくは組織。
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JP2018019440A (ja) * | 2012-03-05 | 2018-02-01 | サムスン エレクトロニクス カンパニー リミテッド | 多重制御チャネルタイプにおける制御チャネルタイプの検出に対応するharq−ack信号送信 |
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