JP2013525332A - ベータ−ENaC−関連疾患を処置するための有機組成物 - Google Patents
ベータ−ENaC−関連疾患を処置するための有機組成物 Download PDFInfo
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- JP2013525332A JP2013525332A JP2013505469A JP2013505469A JP2013525332A JP 2013525332 A JP2013525332 A JP 2013525332A JP 2013505469 A JP2013505469 A JP 2013505469A JP 2013505469 A JP2013505469 A JP 2013505469A JP 2013525332 A JP2013525332 A JP 2013525332A
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- antisense strand
- rnai agent
- enac
- strand
- seq
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Abstract
Description
環境および身体間の粘膜表面は、多数の防御機構を有する。防御の1つの形態は、液体での表面の洗浄である。液体の量は、上皮性液体分泌(しばしば、水および対カチオンイオンに加えてアニオン分泌を反映する)および液体吸収(しばしば、水および対アニオンに加えてNa+吸収を反映する)間のバランスを反映する。粘膜表面の多数の疾患は、分泌(不足)および吸収(過剰)間のアンバランスにより引き起こされる液体不足により引き起こされる。液体層のバランスをとる1つの方法は、Na+チャネル介在液体吸収を減少させることである。
本願発明は、ベータ−ENaC−関連疾患、例えば、嚢胞性線維症、偽性低アルドステロン症1型(PHA1)、リドル症候群、高血圧、アルカローシス、低カリウム血漿および肥満関連高血圧の処置において有用であるベータ−ENaCに対するRNAi剤を含む。本願発明はまた、少なくとも部分的にアルファ−ENaC発現が介在する病理学的状態を有するヒト対象を処置する方法であって、治療有効量のRNAi剤をベータ−ENaCを対象に投与する工程を含む方法を含む。
本願発明は、ベータ−ENaC−関連疾患(例えば、ベータ−ENaCにおける変異と関連する疾患、および/もしくはベータ−ENaCの発現、レベルおよび/または活性を変化させる疾患、ならびに/またはベータ−ENaCの発現、レベルおよび/または活性を調節することにより処置できる疾患)、例えば、嚢胞性線維症、偽性低アルドステロン症1型(PHA1)、リドル症候群、高血圧、アルカローシス、低カリウム血漿および肥満関連高血圧の処置において有用であるベータ−ENaCに対するRNAi剤を含む。本願発明はまた、少なくとも部分的にベータ−ENaC発現が介在する病理学的状態を有するヒト対象を処置する方法であって、治療有効量のRNAi剤 ベータ−ENaCを対象に投与する工程を含む方法を提供する。
表A1.ベータ−ENaCに対するRNAi剤の第1および第2の鎖(例えば、センス(「SS」)およびアンチセンス(「AS」)鎖)の配列番号
実施例1
バイオインフォマティクスおよびベータ−ENaC RNAi剤(siRNA)配列
ベータ−ENaCオリゴヌクレオチド設計を行い、ベータ−ENaC遺伝子[ヒト由来の「ナトリウムチャネル、電位非依存性1ベータ」(NCBIヒト記号SCNN1B)およびカニクイザルおよびラット(ドブネズミ)由来のオルソログ配列]をコードするmRNAを標的とするsiRNAを同定する。設計プロセスは、SCNNB1転写産物ヒト由来のNM_000336.2(NCBI GeneId 6338)、ラット由来のNM_012648.1(NCBI GeneId 24767)および全長カニクイザル配列(本明細書に記載されている)を使用する。
表1.ベータ−ENaC配列
ベータ−ENaC RNAi剤の重複セット
本願発明はまた、重複配列を有するベータ−ENaCに対するRNAi剤のグループに関する。したがって、本願発明は、RNAi剤のグループを含み、ここで、グループ中のそれぞれのRNAi剤は、同じグループ中の他のそれぞれのRNAi剤と少なくとも5、6、7、8、9、10、11、12、13、14、15、16、17、18、19個またはそれ以上のヌクレオチドで重複している。特に、1つの態様において、重複は少なくとも12ntである。
表2.
ベータ−ENaC RNAi剤配列の合成
表1における配列番号:1から110として挙げられている修飾ベータ−ENaC RNAi剤配列を、1μmol規模でMerMade 192 シンセサイザーにて合成する。
ベータ−ENaC RNAi剤のインビトロでのスクリーニング
ベータ−ENaC遺伝子レベルをノックダウンするベータ−ENaC RNAi剤の能力を決定するために、二本鎖をインビトロでのスクリーニングに使用する。
表3.ベータ−ENaCの10nMおよび0.1nMでのノックダウン
表4.ベータ−ENaC用量応答スクリーン
ベータ−ENaC RNAi剤AD−20807およびAD−20832のインビボ分析
インビボ実験において、2つのベータ−ENaC RNAi剤AD−20807およびAD−20832を、ラットにおける全肺におけるベータ−ENaC遺伝子レベルをノックダウンする能力について試験する。該目的は、用量応答を決定することである。免疫刺激も測定する。
表5.
ベータ−ENaC AD−20834のインビボ分析
インビボ実験において、ベータ−ENaC RNAi剤AD20834を、ラットにおける全肺におけるベータ−ENaC遺伝子レベルをノックダウンする能力について試験する。該目的は、用量応答を決定することである。免疫刺激も測定する。
表6.
10mg/kg=200uL容量中に3mgのsiRNA=15mg/mL
3mg/kg=200uL容量中に1mgのsiRNA=5mg/mL
1mg/kg=200uL容量中に0.3mgのsiRNA=1.5mg/mL
ベータ−ENaC RNAi剤の分析
さらなる実験は、Sprague−Dawleyラットにおいてインビボでベータ−ENaC RNAi剤AD20807、AD20832、AD20834、AD20848およびAD20861で行う。ラットを、1日目および2日目にD5Wにおいて10mg/kgで投与し、3日目に殺し、肺を回収する。
ヒト気管支上皮細胞におけるENaCチャネル機能活性に対するベータ−ENaC RNAi剤AD20832のインビトロ効果
ヒト気管支上皮性細胞(HBEC)を、ベータ−ENaC RNAi剤AD20832を含む指示されたsiRNAでトランスフェクトする。トランスフェクト細胞をSnapwellインサート(insert)上に播種し、24時間培養する。次に、上点側の培養培地をそれぞれのインサートから取り出し、細胞を気液界面(ALI)で培養する。細胞を、記載されているとおりALIの8日後にENaCおよびCFTR活性に対してアッセイする。細胞生存能力についてコントロールするために、ENaC機能をCFTR活性に対して標準化し、該データを非トランスフェクトコントロールに対する比較パーセントとして示す(図2A)。さらなる生存能力コントロールとして、膜貫通抵抗性もまた測定する(図2B)。アルファおよびベータENaCサブユニットmRNAの発現分析をそれぞれのインサートに対して行い、GAPDH発現に対して標準化する。(図2C)。該データは、mRNA発現の70%阻害がENaCチャネルの50%機能性阻害を生じるために十分であることを証明する。これは、非トランスフェクト(neg)および非特異的(ns)siRNAコントロールと比較して、アルファまたはベータサブユニットのいずれかのノックダウンについて事実である。該データはまた、ベータENaC siRNAがアルファENaC mRNA発現を阻害しない(逆もまた同様)ことを示す。
センス鎖およびアンチセンス鎖を含むRNAi剤を含む組成物であって、該アンチセンス鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤のアンチセンス鎖と0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、組成物。
a)ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−アデニン−3’(5’−ua−3’)ジヌクレオチド;および/または
b)5’−ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−グアニン−3’(5’−ug−3’)ジヌクレオチド;および/または
c)5’−シチジンが2’−修飾ヌクレオチドである少なくとも1つの5’−シチジン−アデニン−3’(5’−ca−3’)ジヌクレオチド;および/または
d)5’−ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−ウリジン−3’(5’−uu−3’)ジヌクレオチド
を含む、段落[00879]に記載の組成物。
ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−アデニン−3’(5’−ua−3’)ジヌクレオチド;
および/または5’−ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−グアニン−3’(5’−ug−3’)ジヌクレオチド;
および/または5’−シチジンが2’−修飾ヌクレオチドである少なくとも1つの5’−シチジン−アデニン−3’(5’−ca−3’)ジヌクレオチド;
および/または5’−ウリジンが2’−修飾ヌクレオチドである少なくとも1つの5’−ウリジン−ウリジン−3’(5’−uu−3’)ジヌクレオチド
を含む、段落[00899]に記載の組成物。
2’−デオキシ、2’−デオキシ−2’−フルオロ、2’−O−メチル、2’−O−メトキシエチル(2’−O−MOE)、2’−O−アミノプロピル(2’−O−AP)、2’−O−ジメチルアミノエチル(2’−O−DMAOE)、2’−O−ジメチルアミノプロピル(2’−O−DMAP)、2’−O−ジメチルアミノエチルオキシエチル(2’−O−DMAEOE)および2’−O−N−メチルアセトアミド(2’−O−NMA)
からなる群から選択される1つ以上の2’−修飾を含む、段落[00899]に記載の組成物。
Claims (20)
- センス鎖およびアンチセンス鎖を含むRNAi剤を含む組成物であって、該アンチセンス鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤のアンチセンス鎖と0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、組成物。
- ベータ−ENaCに対する第2のRNAi剤をさらに含む、請求項1に記載の組成物。
- RNAi剤が、少なくとも1つの修飾骨格および/または少なくとも1つの2’−修飾ヌクレオチドを含む、請求項1に記載の組成物。
- RNAi剤が、診断化合物、レポーター基、架橋剤、ヌクレアーゼ耐性付与部分、天然もしくは異常核酸塩基、親油性分子、コレステロール、脂質、レクチン、ステロイド、ウバオール(uvaol)、ヘコゲニン、ジオスゲニン、テルペン、トリテルペン、サルササポゲニン、フリーデリン(Friedelin)、エピフリーデラノール誘導体化リトコール酸、ビタミン、炭水化物、デキストラン、プルラン、キチン、キトサン、合成炭水化物、オリゴラクテート(oligo lactate)15−mer、天然ポリマー、低もしくは中間分子量ポリマー、イヌリン、シクロデキストリン、ヒアルロン酸、タンパク質、タンパク質−結合剤、インテグリン標的分子、ポリカチオン、ペプチド、ポリアミン、ペプチド模倣物および/またはトランスフェリンから選択される1つ以上の薬剤に結合している、請求項1に記載の組成物。
- 第1の鎖および第2の鎖を含むRNAi剤を含む組成物であって、該第1の鎖および第2の鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤の第1および第2の鎖のそれぞれと0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、組成物。
- ベータ−ENaCに対する第2のRNAi剤を含む、請求項1に記載の組成物。
- RNAi剤がホスホロチオエートおよび/または2’−修飾ヌクレオチドを含む、請求項1に記載の組成物。
- RNAi剤が、1つ以上の薬剤に結合しており、該薬剤が、診断化合物、レポーター基、架橋剤、ヌクレアーゼ耐性付与部分、天然もしくは異常核酸塩基、親油性分子、コレステロール、脂質、レクチン、ステロイド、ウバオール、ヘコゲニン、ジオスゲニン、テルペン、トリテルペン、サルササポゲニン、フリーデリン、エピフリーデラノール誘導体化リトコール酸、ビタミン、炭水化物、デキストラン、プルラン、キチン、キトサン、合成炭水化物、オリゴラクテート 15−mer、天然ポリマー、低もしくは中間分子量ポリマー、イヌリン、シクロデキストリン、ヒアルロン酸、タンパク質、タンパク質−結合剤、インテグリン標的分子、ポリカチオン、ペプチド、ポリアミン、ペプチド模倣物および/またはトランスフェリンから選択される、請求項1に記載の組成物。
- センス鎖およびアンチセンス鎖を含む治療有効量のRNAi剤を含む組成物を個体に投与する工程を含む該個体におけるベータ−ENaC−関連疾患を処置する方法であって、アンチセンス鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤のアンチセンス鎖と0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、方法。
- ベータ−ENaC−関連疾患が、嚢胞性線維症、偽性低アルドステロン症1型(PHA1)、リドル症候群、高血圧、アルカローシス、低カリウム血漿および/または肥満関連高血圧である、請求項9に記載の方法。
- 嚢胞性線維症、偽性低アルドステロン症1型(PHA1)、リドル症候群、高血圧、アルカローシス、低カリウム血漿および/または肥満関連高血圧に対するさらなる処置を施す工程をさらに含む、請求項9に記載の方法。
- ベータ−ENaCに対するさらなるRNAi剤を投与する工程をさらに含む、請求項11に記載の方法。
- センス鎖およびアンチセンス鎖を含む治療有効量のRNAi剤を含む組成物を個体に投与する工程を含む該個体におけるベータ−ENaC遺伝子の発現を阻害する方法であって、該アンチセンス鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤のアンチセンス鎖と0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、方法。
- ベータ−ENaC−関連疾患が、嚢胞性線維症、偽性低アルドステロン症1型(PHA1)、リドル症候群、高血圧、アルカローシス、低カリウム血漿および/または肥満関連高血圧である、請求項13に記載の方法。
- センス鎖およびアンチセンス鎖を含むRNAi剤を含むRNAi製剤における使用のための医薬であって、該アンチセンス鎖は、表1において提供されるベータ−ENaCに対して特異的なRNAi剤のアンチセンス鎖と0、1、2または3個のヌクレオチドにより異なっている少なくとも15個の連続したヌクレオチドを含む、医薬。
- 薬学的に有効な製剤中の前記いずれかの組成物。
- 個体におけるベータ−ENaC−関連疾患を処置する方法における使用のための請求項1に記載の組成物であって、該方法は、治療有効量の請求項1に記載の組成物を該個体に投与する工程を含む、組成物。
- ベータ−ENaC−関連疾患の処置のための医薬の製造における請求項1に記載の組成物の使用。
- 全てのピリミジンが、2’ O−メチル−修飾ヌクレオチドである、請求項1に記載の組成物。
- 全てのピリミジンが、2’ O−メチル−修飾ヌクレオチドである、請求項5に記載の組成物。
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