JP2013509183A - Pdx−1発現神経内分泌腫瘍中のpdx−1オンコジーンを標的とする新規な治療的rna干渉技術 - Google Patents
Pdx−1発現神経内分泌腫瘍中のpdx−1オンコジーンを標的とする新規な治療的rna干渉技術 Download PDFInfo
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Abstract
Description
U.S.Patent Application No. 2009/0163431: Compositions and Methods for Modulation of PDX-1
U.S.Patent No. 6,716,824: Treatment of Pancreatic Adenocarcinoma by Cytotoxic Gene Therapy
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Claims (47)
- プロモーターと、
前記プロモーターに作動可能に連結されている核酸インサートと
を含む発現ベクターであって、前記核酸インサートが、PDX−1オンコジーンをコードするmRNA転写物の領域とハイブリダイズすることができ、かつ、RNA干渉によってPDX−1オンコジーン発現を阻害する、1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、発現ベクター。 - shRNAに1又は2以上のsiRNA(切断依存性)モチーフ及びmiRNA(切断非依存性)モチーフが組み込まれている、請求項1に記載の発現ベクター。
- shRNAが、PDX−1オンコジーン発現の切断依存性阻害因子でもあり、切断非依存性阻害因子でもある、請求項1に記載の発現ベクター。
- shRNAが二機能性shRNAとしてさらに定義される、請求項1に記載の発現ベクター。
- 1又は2以上のshRNAが、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8及びそれらの組合せ又は修飾形態からなる群から選択される配列を含む、請求項1に記載の発現ベクター。
- 標的とされる領域が、PDX−1オンコジーン転写物の3’UTR領域配列である、請求項1に記載の発現ベクター。
- 治療薬担体と、
プロモーター、及びPDX−1オンコジーンをコードするmRNA転写物の領域とハイブリダイズし、かつ、RNA干渉によってPDX−1オンコジーン発現を阻害する1又は2以上の低分子ヘアピン型RNA(shRNA)をコードする、前記プロモーターに作動可能に連結されている核酸インサートを含む発現ベクターと
を含む治療薬送達系。 - 治療薬担体が凝縮DNAナノ粒子である、請求項7に記載の送達系。
- DNAナノ粒子が、1又は2以上のポリカチオンで凝縮されている、請求項8に記載の送達系。
- 1又は2以上のポリカチオンが、10kDAポリエチレングリコール(PEG)置換システイン−リジン3merペプチド(CK30PEG10k)である、請求項8に記載の送達系。
- 凝縮DNAナノ粒子がさらにリポソーム中に封入されている、請求項8に記載の送達系。
- リポソームが2層中空小胞(BIV)である、請求項11に記載の送達系。
- リポソームが、可逆的にマスクされたリポソームである、請求項11に記載の送達系。
- リポソームが、1又は2以上の「スマート」レセプター標的化部分で装飾されている、請求項11に記載の送達系。
- 1又は2以上の「スマート」レセプター標的化部分が低分子二価βターン模倣体である、請求項14に記載の送達系。
- 治療薬担体がリポソームである、請求項7に記載の送達系。
- リポソームが、1又は2以上の「スマート」レセプター標的化部分で装飾されている2層中空小胞(BIV)であり、前記リポソームが可逆的にマスクされているリポソームである、請求項16に記載の送達系。
- 「スマート」レセプター標的化部分が低分子二価βターン模倣体である、請求項17に記載の送達系。
- 1又は2以上のshRNAが、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8及びそれらの組合せ又は修飾形態からなる群から選択される配列を含む、請求項7に記載の送達系。
- PDX−1オンコジーンを発現する標的組織に1又は2以上のshRNAを送達する方法であって、
プロモーターと、PDX−1オンコジーンをコードするmRNA転写物の領域とハイブリダイズし、かつ、RNA干渉によってPDX−1オンコジーン発現を阻害する前記1又は2以上のshRNAをコードする、前記プロモーターに作動可能に連結されている核酸インサートとを含む発現ベクターを調製するステップと、
前記発現ベクターを治療薬担体と組み合わせるステップであって、前記治療薬担体が1又は2以上の「スマート」レセプター標的化部分で装飾されているリポソームであるステップと、
治療有効量の前記発現ベクターと治療薬担体との複合体を、それを必要とする患者に投与するステップと
を含む方法。 - 治療薬担体が凝縮DNAナノ粒子である、請求項20に記載の方法。
- DNAナノ粒子が1又は2以上のポリカチオンで凝縮されており、前記1又は2以上のポリカチオンが10kDAポリエチレングリコール(PEG)置換システイン−リジン3merペプチド(CK30PEG10k)又は30merリジン縮合ペプチドを含む、請求項21に記載の方法。
- 凝縮DNAナノ粒子がリポソーム中にさらに封入されており、前記リポソームが、2層中空小胞(BIV)であり、1又は2以上の「スマート」レセプター標的化部分で装飾されている、請求項21に記載の方法。
- 1又は2以上の「スマート」レセプター標的化部分が低分子二価βターン模倣体である、請求項23に記載の方法。
- リポソームが、可逆的にマスクされているリポソームである、請求項23に記載の方法。
- リポソームが2層中空小胞(BIV)である、請求項20に記載の方法。
- リポソームが、可逆的にマスクされているリポソームである、請求項20に記載の方法。
- 1又は2以上の「スマート」レセプター標的化部分が低分子二価βターン模倣体である、請求項20に記載の方法。
- 1又は2以上のshRNAが、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8及びそれらの組合せ又は修飾形態からなる群から選択される配列を含む、請求項20に記載の方法。
- 1又は2以上の標的細胞中のPDX−1オンコジーンの発現をサイレンシングする方法であって、
前記1又は2以上の標的細胞を選択するステップと、
前記PDX−1オンコジーンをコードするmRNA転写物の領域とハイブリダイズすることができる1又は2以上の低分子ヘアピン型RNA(shRNA)を発現するベクターを前記標的細胞にトランスフェクトするステップと
を含み、前記1又は2以上の標的細胞への前記ベクターのトランスフェクションがRNA干渉によってPDX−1オンコジーンの発現を阻害する方法。 - shRNAにsiRNA(切断依存性)モチーフ及びmiRNA(切断非依存性)モチーフが組み込まれている、請求項30に記載の方法。
- shRNAが、PDX−1発現の切断依存性阻害因子でもあり、切断非依存性阻害因子でもある、請求項30に記載の方法。
- shRNAが二機能性shRNAとしてさらに定義される、請求項30に記載の方法。
- 標的とされる領域が、PDX−1オンコジーン転写物の3’UTR領域配列である、請求項30に記載の方法。
- 1又は2以上のshRNAが、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8及びそれらの組合せ又は修飾形態からなる群から選択される配列を含む、請求項30に記載の方法。
- ヒト対象における、腫瘍細胞成長の抑制、膵島新生物障害の治療又は両方の方法であって、
腫瘍細胞成長の抑制、膵島新生物障害の治療又は両方を必要とする前記ヒト対象を特定するステップと、
治療薬担体複合体中の発現ベクターを、腫瘍細胞成長の抑制、膵島新生物障害の治療又は両方に十分な量で、前記ヒト対象に投与するステップと
を含み、前記発現ベクターが、PDX−1オンコジーンをコードするmRNA転写物の領域とハイブリダイズすることができる1又は2以上の二機能性低分子ヘアピン型RNA(shRNA)を発現し、前記ハイブリダイゼーションが腫瘍細胞のアポトーシス、増殖停止、又は侵襲性の低下をもたらす方法。 - 膵島新生物障害が、膵臓神経内分泌腫瘍(NET)、インスリノーマ及びカルチノイドを含む、請求項36に記載の方法。
- 二機能性shRNAにsiRNA(切断依存性)モチーフ及びmiRNA(切断非依存性)モチーフが組み込まれている、請求項36に記載の方法。
- 二機能性shRNAが、PDX−1発現の切断依存性阻害因子でもあり、切断非依存性阻害因子でもある、請求項36に記載の方法。
- 1又は2以上のshRNAが、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8及びそれらの組合せ又は修飾形態からなる群から選択される配列を含む、請求項36に記載の方法。
- 標的とされる領域が、PDX−1転写物の3’UTR領域配列である、請求項36に記載の方法。
- 膵島新生物障害が、膵臓神経内分泌腫瘍(NET)である、請求項36に記載の方法。
- 治療薬担体が、凝縮DNAナノ粒子、又は1若しくは2以上の「スマート」レセプター標的化部分で装飾された、可逆的にマスクされたリポソームである、請求項36に記載の方法。
- DNAナノ粒子が、1又は2以上のポリカチオンで凝縮されており、前記1又は2以上のポリカチオンが、10kDAポリエチレングリコール(PEG)置換システイン−リジン3merペプチド(CK30PEG10k)又は30merリジン縮合ペプチドである、請求項43に記載の方法。
- 可逆的にマスクされたリポソームが2層中空小胞(BIV)である、請求項43に記載の方法。
- 1又は2以上の「スマート」レセプター標的化部分が低分子二価βターン模倣体である、請求項43に記載の方法。
- 凝縮DNAナノ粒子がリポソーム中にさらに封入されている、請求項43に記載の方法。
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JP6007103B2 (ja) | 2016-10-12 |
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HK1176964A1 (zh) | 2013-08-09 |
IL238977A (en) | 2016-10-31 |
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US8361983B2 (en) | 2013-01-29 |
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JP2014207907A (ja) | 2014-11-06 |
EP2507374A2 (en) | 2012-10-10 |
WO2011053660A3 (en) | 2011-10-06 |
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US20130084331A1 (en) | 2013-04-04 |
TW201125594A (en) | 2011-08-01 |
US20110117183A1 (en) | 2011-05-19 |
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