JP2020533978A - グルコース依存性の生存率を介して、細菌が固形腫瘍を特異的に標的とすることを可能にする核酸システム - Google Patents
グルコース依存性の生存率を介して、細菌が固形腫瘍を特異的に標的とすることを可能にする核酸システム Download PDFInfo
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Abstract
Description
112:矢印
120:薬物送達システム
122:細菌
124:抗癌薬
330:肝臓切片
Claims (35)
- 細菌株に導入されて、固形腫瘍において増殖するが非腫瘍組織においては増殖しない遺伝子操作された細菌株を生成する核酸システムであって、
前記遺伝子操作された細菌株を死滅させる毒素を発現する毒素遺伝子をコードする第1のDNA断片と、
前記毒素を無効にする解毒剤を発現する解毒剤遺伝子をコードする第2のDNA断片と、
グルコースが前記解毒剤遺伝子の転写を抑制するように、前記解毒剤遺伝子の前記転写を制御する第1のプロモーターと、
前記毒素遺伝子の構成的発現を引き起こす第1の構成的プロモーターと、を含み、
前記第2のDNA断片は、前記固形腫瘍において転写されるが、前記非腫瘍組織においては転写されない、核酸システム。 - 前記固形腫瘍は、0.424mMよりも低いグルコース濃度で特徴付けられる、請求項1に記載の核酸システム。
- 前記非腫瘍組織は、1.22mMよりも高いグルコース濃度で特徴付けられる、請求項1〜2のいずれか1項に記載の核酸システム。
- 前記第1のプロモーターは、前記第2のDNA断片のすぐ上流に位置する、請求項1〜3のいずれか1項に記載の核酸システム。
- 前記第1の構成的プロモーターは、前記第1のDNA断片のすぐ上流に位置する、請求項1〜4のいずれか1項に記載の核酸システム。
- 前記第1のプロモーターは、lacプロモーター、gltAプロモーター、sdhADCプロモーター及びtnaBプロモーターからなる群から選択される、請求項1〜5のいずれか1項に記載の核酸システム。
- 一対の前記毒素と前記解毒剤は、CcdB−CcdA対、AvrRxo1−Arc1対、Hha−TomB対、及びPaaA2−ParE2対からなる群から選択される、請求項1〜6のいずれか1項に記載の核酸システム。
- 前記第1のDNA断片は、配列番号1に示され、前記第2のDNA断片は、配列番号2に示される、請求項1〜7のいずれか1項に記載の核酸システム。
- 前記第1のプロモーターは、配列番号3に示される、請求項1〜8のいずれか1項に記載の核酸システム。
- 5〜6個のヌクレオチドからなり、前記第2のDNA断片のすぐ上流に位置する前記遺伝子操作された細菌株の元の5〜6個のヌクレオチドを置き換えるランダム配列をさらに含む、請求項1〜9のいずれか1項に記載の核酸システム。
- 前記ランダム配列は、GCCTT又はTGTCTである、請求項10に記載の核酸システム。
- クロラムフェニコール耐性カセットをコードする第3のDNA断片をさらに含み、
前記第3のDNA断片は、配列番号4に示される、請求項1〜11のいずれか1項に記載の核酸システム。 - 前記細菌株は、大腸菌、サルモネラ菌及び赤痢菌からなる群から選択される、請求項1〜12のいずれか1項に記載の核酸システム。
- 前記細菌株は、大腸菌MG1655である、請求項1〜13のいずれか1項に記載の核酸システム。
- 配列番号7又は配列番号8に示される、請求項1〜14のいずれか1項に記載の核酸システム。
- 細菌株に導入されて、固形腫瘍において増殖するが非腫瘍組織においては増殖しない遺伝子操作された細菌株を生成する核酸システムであって、
前記遺伝子操作された細菌株を死滅させる毒素を発現する毒素遺伝子をコードする第1のDNA断片と、
前記毒素を無効にする解毒剤を発現する解毒剤遺伝子をコードする第2のDNA断片と、
グルコースが前記毒素遺伝子の転写を誘導するように、前記毒素遺伝子の前記転写を制御する第2のプロモーターと、
前記解毒剤遺伝子の構成的発現を引き起こす第2の構成的プロモーターと、を含み、
前記第1のDNA断片は、前記非腫瘍組織において転写されるが、前記固形腫瘍においては転写されない、核酸システム。 - 前記固形腫瘍は、0.424mMよりも低いグルコース濃度で特徴付けられる、請求項16に記載の核酸システム。
- 前記非腫瘍組織は、1.22mMよりも高いグルコース濃度で特徴付けられる、請求項16〜17のいずれか1項に記載の核酸システム。
- 前記第2のプロモーターは、前記第1のDNA断片のすぐ上流に位置する、請求項16〜18のいずれか1項に記載の核酸システム。
- 前記第2の構成的プロモーターは、前記第2のDNA断片のすぐ上流に位置する、請求項16〜19のいずれか1項に記載の核酸システム。
- 前記第2のプロモーターは、ptsGのプロモーター、fruBのプロモーター、及びackAのプロモーターからなる群から選択される、請求項16〜20のいずれか1項に記載の核酸システム。
- 一対の前記毒素と前記解毒剤は、CcdB−CcdA対、AvrRxo1−Arc1対、Hha−TomB対、及びPaaA2−ParE2対からなる群から選択される、請求項16〜21のいずれか1項に記載の核酸システム。
- 前記第1のDNA断片は、配列番号1に示され、前記第2のDNA断片は、配列番号2に示される、請求項16〜22のいずれか1項に記載の核酸システム。
- 5〜6個のヌクレオチドからなり、前記第1のDNA断片のすぐ上流に位置する前記遺伝子操作された細菌株の元の5〜6個のヌクレオチドを置き換えるランダム配列をさらに含む、請求項16〜23のいずれか1項に記載の核酸システム。
- クロラムフェニコール耐性カセットをコードする第3のDNA断片をさらに含み、
前記第3のDNA断片は、配列番号4に示される、請求項16〜24のいずれか1項に記載の核酸システム。 - 前記細菌株は、大腸菌、サルモネラ菌及び赤痢菌からなる群から選択される、請求項16〜25のいずれか1項に記載の核酸システム。
- 前記細菌株は、大腸菌MG1655である、請求項16〜26のいずれか1項に記載の核酸システム。
- 腫瘍を標的とする遺伝子操作された細菌株を構築する方法であって、
前記遺伝子操作された細菌株を死滅させる毒素を発現する毒素遺伝子をコードする第1のDNA断片と、
前記毒素を無効にする解毒剤を発現する解毒剤遺伝子をコードする第2のDNA断片と、
グルコースが前記解毒剤遺伝子の転写を抑制するように、前記解毒剤遺伝子の前記転写を制御する第1のプロモーターと、
前記毒素遺伝子の構成的発現を引き起こす第1の構成的プロモーターと、
を含む核酸システムを、細菌株に挿入することと、
前記核酸システムを含む前記遺伝子操作された細菌株のクローンを培養することと、
グルコースの非存在下で増殖するがグルコースの存在下では増殖しない前記クローンを選択することにより、前記腫瘍を標的とする前記遺伝子操作された細菌株を取得することと、を含み、
前記第2のDNA断片は、前記固形腫瘍において転写されるが、前記非腫瘍組織においては転写されない、方法。 - 5〜6個のヌクレオチドからなるランダム配列を挿入して、前記第2のDNA断片のすぐ上流に位置する天然ヌクレオチドを置き換えることによって、前記核酸システムのランダムライブラリを生成することをさらに含む、請求項28に記載の方法。
- 0mMのグルコース濃度で増殖するが、5mMのグルコース濃度では増殖しない前記クローンは、前記腫瘍を標的とする前記遺伝子操作された細菌株として選択される、請求項28〜29のいずれか1項に記載の方法。
- 前記核酸システムは、請求項1〜15のいずれか1項に記載の核酸システムである、請求項28〜30のいずれか1項に記載の方法。
- 腫瘍を標的とする遺伝子操作された細菌株を構築する方法であって、
前記遺伝子操作された細菌株を死滅させる毒素を発現する毒素遺伝子をコードする第1のDNA断片と、
前記毒素を無効にする解毒剤を発現する解毒剤遺伝子をコードする第2のDNA断片と、
グルコースが前記毒素遺伝子の転写を誘導するように、前記毒素遺伝子の前記転写を制御する第2のプロモーターと、
前記解毒剤遺伝子の構成的発現を引き起こす第2の構成的プロモーターと、
を含む核酸システムを、細菌株に挿入することと、
前記核酸システムを含む前記遺伝子操作された細菌株のクローンを培養することと、
グルコースの非存在下で増殖するがグルコースの存在下では増殖しない前記クローンを選択することにより、前記腫瘍を標的とする前記遺伝子操作された細菌株を取得することと、を含み、
前記第1のDNA断片は、前記非腫瘍組織において転写されるが、前記固形腫瘍においては転写されない、方法。 - 5〜6個のヌクレオチドからなるランダム配列を挿入して、前記第1のDNA断片のすぐ上流に位置する天然ヌクレオチドを置き換えることによって、前記核酸システムのランダムライブラリを生成することをさらに含む、請求項32に記載の方法。
- 0mMのグルコース濃度で増殖するが、5mMのグルコース濃度では増殖しない前記クローンは、前記腫瘍を標的とする前記遺伝子操作された細菌株として選択される、請求項32〜33のいずれか1項に記載の方法。
- 前記核酸システムは、請求項16〜27のいずれか1項に記載の核酸システムである、請求項32〜34のいずれか1項に記載の方法。
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