JP2016516003A - 眼内透過性亢進の予防及び治療におけるsema3aの阻害 - Google Patents
眼内透過性亢進の予防及び治療におけるsema3aの阻害 Download PDFInfo
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Abstract
Description
本出願は、米国特許法第119条(e)に基づき、2013年2月21日に出願された米国仮出願第61/767,419号の優先権を主張するものであり、当該出願は、その全体が参照により本明細書に組み込まれる。
本出願は、「12810_496_ST25」という名称で2014年2月21日に作成された222キロバイトのサイズを有するコンピュータ読取り可能な形式の配列表を含み、当該配列表は、参照により本明細書に組み込まれる。
(a)Sema3Aの核酸もしくはSema3Aをコードしたポリペプチドの発現レベル、
(b)Sema3Aの活性レベル、
(c)Sema3A活性によって生じた分子のレベル、または
(d)(a)から(c)の任意の組み合わせ
が、試験化合物が存在しない場合と比較して、試験化合物の存在下で減少するかどうかを決定することを含む。この減少は、当該試験化合物が網膜血管透過性亢進の予防及び治療に有用である可能性を示すものである。一実施形態において、上述の方法は、インビトロ法である。一実施形態において、Sema3A活性は、Sema3AのNrp−1受容体への結合である。さらなる実施形態において、Sema3A活性は、血管透過性の増加である。
a)試験化合物を、レポータタンパク質をコードすることができるレポータ遺伝子を含有する第2の核酸と機能的に連結させた、Sema3A遺伝子に通常関連した転写調節エレメント(たとえば、内在性プロモータまたはその断片)を含有する第1の核酸を含む細胞に接触させること、及び
b)レポータ遺伝子の発現またはレポータ活性が試験化合物の存在下で減少するかどうかを決定することを含む。
レポータ遺伝子の発現またはレポータ遺伝子の活性の減少は、当該試験化合物が血管透過性亢進を減少させるため(たとえば、非増殖性糖尿病網膜症及び黄斑浮腫の治療または予防)に使用できる可能性を示す。
定義
血管透過性亢進を治療または予防するための方法
Sema3A媒介細胞活性の阻害
a.抗体
b.可溶性Nrp−1受容体またはその断片
Sema3A発現の阻害
医薬組成物
投与経路
組成物/製剤
有効用量
パッケージ
スクリーニングアッセイ
(a)Sema3Aの核酸もしくはSema3Aをコードしたポリペプチドの発現レベル、
(b)Sema3Aの活性レベル、
(c)Sema3A活性によって生じた分子のレベル、または
(d)(a)から(c)の任意の組み合わせ
が、試験化合物が存在しない場合と比較して、前記試験化合物の存在下で減少するかどうかを決定することを含む。この減少は、当該試験化合物が網膜血管透過性亢進の予防及び治療に有用である可能性を示すものである。一実施形態において、上述の方法は、インビトロ法である。一実施形態において、Sema3A活性は、Sema3AのNrp−1受容体への結合である。さらなる実施形態において、Sema3A活性は、血管透過性の増加である。
材料及び方法
ヒト試料
Maisonneuve−Rosemont Hospital(HMR)倫理委員会によるヒト臨床試験実施要項及び同意説明文書の承認、ならびにT1DM罹患患者からの局所硝子体生検標本を得るための患者募集。
動物
ストレプトゾトシン(STZ)マウスモデル
リアルタイムPCR分析
レーザマイクロダイセクション
ウエスタンブロット法
免疫組織化学
レンチウイルスの調製
可溶性組換えNRP1及びマウス抗VEGF
統計的分析
実施例2
糖尿病網膜症に罹患しているヒト患者硝子体におけるSema3Aの上昇
実施例3
ストレプトゾトシン誘発糖尿病の初期段階における神経性Sema3Aの上方制御
実施例4
糖尿病網膜症における役割と地図的に一致するSema3Aの発現パターン
実施例5
Sema3Aによる網膜バリア機能の弱体化
実施例6
ニューロン誘導性Sema3Aの阻害によるT1DMの血管透過性の効果的な減少
実施例7
Sema3Aの硝子体内中和による網膜血管透過性の減少
実施例8
Nrp−1条件付きノックアウトマウスでのSema3A誘発性網膜バリア機能破綻の阻害
参考文献
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Claims (31)
- Sema3Aを介する眼内血管透過性亢進を阻害することを含む、対象の黄斑浮腫を予防または治療するための方法。
- Sema3Aを介する眼内血管透過性亢進を阻害することを含む、対象の血液網膜関門の腫脹を予防または抑制するための方法。
- 前記黄斑浮腫が実質的に非増殖性である、請求項1に記載の方法。
- 前記黄斑浮腫が糖尿病黄斑浮腫である、請求項1に記載の方法。
- 前記糖尿病黄斑浮腫が実質的に非増殖性である、請求項4に記載の方法。
- 前記対象が非増殖性黄斑浮腫に罹患している、請求項1〜5のいずれか一項に記載の方法。
- 前記対象がVEGF誘発前の初期糖尿病に罹患している、請求項1〜6のいずれか一項に記載の方法。
- 前記対象が血液網膜関門の腫脹を患っている、請求項1〜6のいずれか一項に記載の方法。
- 前記対象のVEGFが実質的に正常レベルである、請求項1〜8のいずれか一項に記載の方法。
- 前記対象が実質的な周皮細胞の損失を患っていない、請求項1〜9のいずれか一項に記載の方法。
- 前記対象に自覚症状がない、請求項1〜10のいずれか一項に記載の方法。
- 前記対象が網膜腫脹と診断されている、請求項1〜11のいずれか一項に記載の方法。
- 前記方法が、予防的または治療的に有効な量のSema3Aアンタゴニストを投与することを含む、請求項1〜12のいずれか一項に記載の方法。
- 前記アンタゴニストが、
i)抗Sema3A抗体、
ii)抗Nrp−1抗体、
iii)Sema3AのアンチセンスもしくはshRNA、
iv)Npr−1のアンチセンスもしくはshRNA、及び/または
v)可溶性のNrp−1ポリペプチドもしくはその断片
である、請求項13に記載の方法。 - 前記Nrp−1抗体または前記可溶性NRP−ポリペプチドもしくはその断片が、VEGFのNrp−1への結合を実質的に減少させない、請求項14に記載の方法。
- 前記Nrp−1抗体がNrp−1のa1a2ドメインに結合する、請求項14または15に記載の方法。
- 前記Nrp−1断片がNrp−1のa1a2ドメインからなる、請求項14または15に記載の方法。
- 前記Sema3A抗体が、Sema3AのNrp−1結合ドメインに結合する、請求項14に記載の方法。
- Sema3Aアンタゴニストを含む、黄斑浮腫の予防または治療のための組成物。
- Sema3Aアンタゴニストを含む、血液網膜関門の腫脹の予防または治療のための組成物。
- 前記黄斑浮腫が糖尿病黄斑浮腫である、請求項20に記載の組成物。
- 前記黄斑浮腫が実質的に非増殖性糖尿病黄斑浮腫である、請求項21に記載の組成物。
- 前記アンタゴニストが、
i)抗Sema3A抗体、
ii)抗Nrp−1抗体、
iii)Sema3AのアンチセンスもしくはshRNA、
iv)Npr−1のアンチセンスもしくはshRNA、及び/または
v)可溶性のNrp−1ポリペプチドもしくはその断片
である、請求項21または22に記載の組成物。 - 前記Sema3AアンタゴニストがNrp−1へのVEGF結合を減少させない、請求項23に記載の組成物。
- 前記アンタゴニストが、VEGFに実質的に結合しない可溶性Nrp−1断片である、請求項23に記載の組成物。
- 黄斑浮腫の予防または治療のためのSema3Aアンタゴニストを含む組成物の使用。
- 血液網膜関門の腫脹の予防または抑制のためのSema3Aアンタゴニストを含む組成物の使用。
- 前記浮腫が糖尿病黄斑浮腫である、請求項26に記載の使用。
- 前記アンタゴニストが、
i)抗Sema3A抗体、
ii)抗Nrp−1抗体、
iii)Sema3AのアンチセンスもしくはshRNA、
iv)Npr−1のアンチセンスもしくはshRNA、及び/または
v)可溶性のNrp−1ポリペプチドもしくはその断片
である、請求項26〜28のいずれか一項に記載の使用。 - Sema3Aを介する眼内血管透過性亢進を予防または治療するために潜在的に有用な化合物を特定するための方法であって、
i)Sema3Aの核酸もしくはSema3Aをコードしたポリペプチドの発現レベル、
ii)b)Sema3Aの受容体活性レベル、または
iii)c)i)及びii)の組み合わせ
が、試験化合物が存在しない場合と比較して、前記試験化合物の存在下で減少するかどうかを決定することを含み、前記減少は、前記試験化合物がSema3Aを介する眼内血管透過性亢進を予防または治療するために潜在的に有用であることを示す、方法。 - Sema3Aを介する眼内血管透過性亢進を予防または治療するための化合物を特定または特徴付けるための方法であって、
i)試験化合物を、レポータタンパク質をコードすることができるレポータ遺伝子を含有する第2の核酸と機能的に連結させた、Sema3A遺伝子と通常関連した第1の転写調節エレメントを含有する第1の核酸を含む細胞に接触させること、及び
ii)レポータ遺伝子の発現またはレポータ活性が前記試験化合物の存在下で減少するかどうかを決定することを含み、
前記レポータ遺伝子の発現またはレポータ遺伝子の活性の減少は、前記試験化合物がSema3Aを介する眼内血管透過性亢進を予防または治療するために有用であり得ることを示す、方法。
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