JP7291423B2 - AIMP2-DX2およびmiR-142の標的核酸を含むベクター、ならびにその使用 - Google Patents
AIMP2-DX2およびmiR-142の標的核酸を含むベクター、ならびにその使用 Download PDFInfo
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Description
本出願とともに提出された、ASCIIテキストファイルにおいて電子提出された配列表(ファイル名: 2493-0003WO01- Sequence Listing_ST25.txt;サイズ: 6KB;および作成日: 2020年3月16日)の内容は、その全体において本明細書に参考として援用される。
AIMP2-DX2およびmiR-142の標的配列を含むベクター、ならびにその使用が、本明細書で開示される。
哺乳動物の脳は、神経幹細胞の分裂、分化、生存および死滅を含む一連のプロセス、ならびにシナプスの形成などを受けた後、全身の神経ネットワークの確立を通じて複雑な機能を実施し得る。動物の脳におけるニューロンは、それらが成熟した状態の間ですら、神経の成長において必要な広い範囲の物質を連続して生成し、それによって、軸索および樹状突起の成長を誘導する。さらに、それらは連続して分化を受けるといわれている。なぜなら新たな学習および記憶が実施されるときには常に、神経ネットワークの絶え間ないシナプス再編およびシナプス接続が存在するからである。ニューロンは、これらが、ストレスに起因する、細胞分化およびシナプス形成およびアポトーシスのプロセスにおいて、標的由来生存因子(例えば、神経成長因子)を受容できない場合に、アポトーシスを受け、細胞傷害性薬剤は、脳変性障害の主要な原因になる。動物の末梢神経系が損傷される場合、中枢神経系とは異なり、軸索は、長期間にわたって再生される。損傷した神経の背後にある軸索は、ワーラー変性として公知のプロセスによって変性され、神経の細胞本体は、軸索の再成長を再び開始すると同時に、シュワン細胞が、再生プロセス(分裂後の生存および消失を経て標的神経の決定、その後、分化などを再び受けることを含む)を受けた後に再生される。
AIMP2-DX2が、神経疾患を処置するにあたって有用であり得ることもまた、決定されている(KR10-2015-0140723(2017)およびUS2019/0298858(2019年10月23日公開))。
miR-142を標的化する配列(例えば、miR-142-3pおよび/またはmiR-142-5p標的核酸)を含む組換えベクターは、AIMP2スプライス改変体の発現を、神経組織および脳組織において選択的に制御し得る。
AIMP2-DX2は、アポトーシスと関連する、腫瘍抑制因子AIMP2の選択的スプライシング改変体である。AIMP2-DX2は、AIMP2の機能を抑制することによって、腫瘍のアポトーシスを阻害することが公知である。
1)プロモーター;
2)プロモーターに作動可能に連結された標的タンパク質をコードする塩基配列;および
3)前記塩基配列の3’UTRに挿入されたmiR-142-3p標的塩基配列を含む発現カセット、
を含む実施形態。
CD45の大部分は、造血細胞の膜貫通プロテインチロシンホスファターゼであり、これは、細胞表面上の上記分子に従って上記細胞を定義するために使用され得る。CD45は、全ての白血球群およびBリンパ球のマーカーである。本発明者らは、CD45由来細胞、特に、リンパ球および白血球範囲の細胞において発現されることなく、ニューロンにおいてのみ特異的に発現される組換えベクターを生成した。その組換えベクターは、アミノアシルtRNAシンセターゼ複合体相互作用多機能タンパク質2(AIMP2)のエキソン2が欠失しているスプライス改変体を含み、AIMP2スプライス改変体の発現を制御し得るmiRNAを挿入することによる。
2-1. インビトロ条件下でのニューロン特異的発現効果の確認
3-1. qRT-PCR
4-1. コア結合配列の阻害効果のために生成した3タイプのベクター
実施例2において、HEK293T細胞を、組換えAAV2粒子を生成するために必要な構成要素の全てをコードするOxgene(UK)の3種のプラスミドで共トランスフェクトした。
本発明は、例えば、以下の項目を提供する。
(項目1)
エキソン2欠失AIMP2改変体(AIMP2-DX2)遺伝子およびmiR-142標的核酸を含む、組換えベクター。
(項目2)
前記AIMP2-DX2に作動可能に連結されたプロモーターをさらに含む、項目1に記載のベクター。
(項目3)
前記プロモーターは、レトロウイルス(LTR)プロモーター、サイトメガロウイルス(CMV)プロモーター、ラウス肉腫ウイルス(RSV)プロモーター、MTプロモーター、EF-1アルファプロモーター、UB6プロモーター、ニワトリβ-アクチンプロモーター、CAGプロモーター、RPE65プロモーターまたはオプシンプロモーターである、項目2に記載のベクター。
(項目4)
前記miR-142標的核酸は、前記AIMP2-DX2遺伝子に対して3’側にある、項目1~3のいずれか1項に記載のベクター。
(項目5)
前記AIMP2-DX2遺伝子は、配列番号2と少なくとも90%同一であるアミノ酸配列をコードするヌクレオチド配列を有する、項目1~4のいずれか1項に記載のベクター。
(項目6)
前記AIMP2-DX2遺伝子は、配列番号2のアミノ酸配列をコードするヌクレオチド配列を有する、項目5に記載のベクター。
(項目7)
前記AIMP2-DX2遺伝子は、配列番号1のヌクレオチド配列と少なくとも90%同一であるヌクレオチド配列を有する、項目1~4のいずれか1項に記載のベクター。
(項目8)
前記AIMP2-DX2遺伝子は、配列番号1のヌクレオチド配列を有する、項目7に記載のベクター。
(項目9)
前記miR-142標的核酸は、ACACTAを含むヌクレオチド配列を含む、項目1~8のいずれか1項に記載のベクター。
(項目10)
前記miR-142標的核酸は、ACACTAおよび配列番号5の1~17個のさらなる連続するヌクレオチドを含むヌクレオチド配列を含む、項目9に記載のベクター。
(項目11)
前記miR-142標的核酸は、配列番号5のヌクレオチド配列(TCCATAAAGTAGGAAACACTACA)と少なくとも50%同一のヌクレオチド配列を含む、項目1~8のいずれか1項に記載のベクター。
(項目12)
前記miR-142標的核酸は、配列番号5のヌクレオチド配列を含む、項目11に記載のベクター。
(項目13)
前記miR-142標的核酸は、ACTTTAを含むヌクレオチド配列を含む、項目1~8のいずれか1項に記載のベクター。
(項目14)
前記miR-142標的核酸は、ACTTTAおよび配列番号7の1~15個のさらなる連続するヌクレオチドを含むヌクレオチド配列を含む、項目13に記載のベクター。
(項目15)
前記miR-142標的核酸は、配列番号7のヌクレオチド配列(AGTAGTGCTTTCTACTTTATG)と少なくとも50%同一のヌクレオチド配列を含む、項目1~8のいずれか1項に記載のベクター。
(項目16)
前記miR-142標的核酸は、配列番号7のヌクレオチド配列を含む、項目15に記載のベクター。
(項目17)
前記miR-142標的核酸は、2~10回反復される、項目1~16のいずれか1項に記載のベクター。
(項目18)
前記ベクターは、ウイルスベクターである、項目1~17のいずれか1項に記載のベクター。
(項目19)
前記ウイルスベクターは、アデノウイルス、アデノ随伴ウイルス、レンチウイルス、レトロウイルス、ヒト免疫不全ウイルス(HIV)、MLV(マウス白血病ウイルス)、ASLV(トリ肉腫/白血病)、SNV(脾臓壊死ウイルス)、RSV(ラウス肉腫ウイルス)、MMTV(マウス乳房腫瘍ウイルス)、または単純ヘルペスウイルスベクターである、項目18に記載のベクター。
(項目20)
前記ウイルスベクターは、アデノ随伴ウイルス(AAV)、アデノウイルス、レンチウイルス、レトロウイルス、ワクシニアウイルス、または単純ヘルペスウイルスベクターである、項目18に記載のベクター。
(項目21)
神経疾患の処置の必要性のある被験体において神経疾患を処置する方法であって、前記方法は、項目1~20のいずれか1項に記載のベクターを投与する工程を包含する、方法。
(項目22)
前記神経疾患は、筋萎縮性側索硬化症(ALS)、アルツハイマー病、パーキンソン病、網膜変性、軽度認知障害、多発梗塞性認知症、前頭側頭葉型認知症、レビー小体型認知症、ハンチントン病、神経変性疾患、代謝性脳障害、鬱病、てんかん、多発性硬化症、大脳皮質基底核変性症、多系統萎縮症、進行性核上性麻痺、歯状核赤核淡蒼球ルイ体萎縮症、脊髄小脳失調症、原発性側索硬化症、脊髄性筋萎縮症、または脳卒中である、項目21に記載の方法。
(項目23)
前記神経疾患は、ALSである、項目22に記載の方法。
(項目24)
前記処置は、運動活動を改善するか、または前記被験体の寿命を延ばす、項目23に記載の方法。
(項目25)
前記ベクターは、脳または脊髄に投与される、項目21~24のいずれかに記載の方法。
(項目26)
前記ベクターは、定位固定注射によって脳に投与される、項目25に記載の方法。
Claims (20)
- エキソン2欠失AIMP2改変体(AIMP2-DX2)遺伝子およびmiR-142標的核酸を含む、組換えベクター。
- 前記AIMP2-DX2に作動可能に連結されたプロモーターをさらに含む、請求項1に記載のベクター。
- 前記プロモーターは、レトロウイルス(LTR)プロモーター、サイトメガロウイルス(CMV)プロモーター、ラウス肉腫ウイルス(RSV)プロモーター、MTプロモーター、EF-1アルファプロモーター、UB6プロモーター、ニワトリβ-アクチンプロモーター、CAGプロモーター、RPE65プロモーターまたはオプシンプロモーターである、請求項2に記載のベクター。
- 前記miR-142標的核酸は、前記AIMP2-DX2遺伝子に対して3’側にある、請求項1~3のいずれか1項に記載のベクター。
- 前記AIMP2-DX2遺伝子は、配列番号2と少なくとも90%同一であるアミノ酸配列をコードするヌクレオチド配列を有する、請求項1~4のいずれか1項に記載のベクター。
- 前記AIMP2-DX2遺伝子は、配列番号2のアミノ酸配列をコードするヌクレオチド配列を有する、請求項5に記載のベクター。
- 前記AIMP2-DX2遺伝子は、配列番号1のヌクレオチド配列と少なくとも90%同一であるヌクレオチド配列を有する、請求項1~4のいずれか1項に記載のベクター。
- 前記AIMP2-DX2遺伝子は、配列番号1のヌクレオチド配列を有する、請求項7に記載のベクター。
- 前記miR-142標的核酸は、ACACTAを含むヌクレオチド配列を含む、請求項1~8のいずれか1項に記載のベクター。
- 前記miR-142標的核酸は、ACACTAおよび配列番号5の1~17個のさらなる連続するヌクレオチドを含むヌクレオチド配列を含む、請求項9に記載のベクター。
- 前記miR-142標的核酸は、配列番号5のヌクレオチド配列(TCCATAAAGTAGGAAACACTACA)と少なくとも90%同一のヌクレオチド配列を含み、ここで、前記miR-142標的核酸は、AIMP2-DX2発現を抑制する、請求項1~8のいずれか1項に記載のベクター。
- 前記miR-142標的核酸は、配列番号5のヌクレオチド配列を含む、請求項11に記載のベクター。
- 前記miR-142標的核酸は、ACTTTAを含むヌクレオチド配列を含む、請求項1~8のいずれか1項に記載のベクター。
- 前記miR-142標的核酸は、ACTTTAおよび配列番号7の1~15個のさらなる連続するヌクレオチドを含むヌクレオチド配列を含む、請求項13に記載のベクター。
- 前記miR-142標的核酸は、配列番号7のヌクレオチド配列(AGTAGTGCTTTCTACTTTATG)と少なくとも90%同一のヌクレオチド配列を含み、ここで、前記miR-142標的核酸は、AIMP2-DX2発現を抑制する、請求項1~8のいずれか1項に記載のベクター。
- 前記miR-142標的核酸は、配列番号7のヌクレオチド配列を含む、請求項15に記載のベクター。
- 前記miR-142標的核酸は、2~10回反復される、請求項1~16のいずれか1項に記載のベクター。
- 前記ベクターは、ウイルスベクターである、請求項1~17のいずれか1項に記載のベクター。
- 前記ウイルスベクターは、アデノウイルス、アデノ随伴ウイルス、レンチウイルス、レトロウイルス、ヒト免疫不全ウイルス(HIV)、MLV(マウス白血病ウイルス)、ASLV(トリ肉腫/白血病)、SNV(脾臓壊死ウイルス)、RSV(ラウス肉腫ウイルス)、MMTV(マウス乳房腫瘍ウイルス)、または単純ヘルペスウイルスベクターである、請求項18に記載のベクター。
- 前記ウイルスベクターは、アデノ随伴ウイルス(AAV)、アデノウイルス、レンチウイルス、レトロウイルス、ワクシニアウイルス、または単純ヘルペスウイルスベクターである、請求項18に記載のベクター。
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KR10-2019-0030126 | 2019-03-15 | ||
PCT/IB2020/052395 WO2020188472A1 (en) | 2019-03-15 | 2020-03-16 | Vectors containing aimp2-dx2 and target nucleic acids for mir-142 and uses thereof |
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KR20230110503A (ko) * | 2020-09-30 | 2023-07-24 | 주식회사 제너로스 | AIMP2-DX2 및 선택적으로 miR-142에 대한 표적 서열 및 이의 조성물을 이용한 노인성 황반 질환의 치료방법 |
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WO2023218430A1 (en) * | 2022-05-13 | 2023-11-16 | Generoath Co., Ltd. | Methods of treating retinal degenerative diseases using aimp2-dx2 and optionally a target sequence for mir‑142 and compositions thereof |
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US7459529B2 (en) * | 2004-11-24 | 2008-12-02 | Seoul National University Industry Foundation | AIMP2-DX2 and its uses |
US8003780B2 (en) * | 2004-11-24 | 2011-08-23 | Neomics Co., Ltd. | AIMP2-DX2 gene and SiRNA targeting AIMP2-DX2 |
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