JPWO2020152869A1 - 線維症治療剤 - Google Patents
線維症治療剤 Download PDFInfo
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- JPWO2020152869A1 JPWO2020152869A1 JP2020567348A JP2020567348A JPWO2020152869A1 JP WO2020152869 A1 JPWO2020152869 A1 JP WO2020152869A1 JP 2020567348 A JP2020567348 A JP 2020567348A JP 2020567348 A JP2020567348 A JP 2020567348A JP WO2020152869 A1 JPWO2020152869 A1 JP WO2020152869A1
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Abstract
Description
〔1〕 NEK6遺伝子の発現を抑制するアンチセンス核酸を有効成分として含むSMAD2/3タンパク質のリン酸化阻害剤;
〔2〕 NEK6遺伝子の発現を抑制するアンチセンス核酸を有効成分として含む線維症治療剤;
〔3〕 線維症が肺線維症、肝線維症又は腎線維症である、〔2〕の治療剤;
〔4〕 配列番号1の配列と少なくとも90%の配列同一性を有する配列、配列番号2の配列と少なくとも90%の配列同一性を有する配列及び配列番号3の配列と少なくとも90%の配列同一性を有する配列からなる群より選択される配列を含む、NEK6遺伝子の発現を抑制するアンチセンス核酸;
〔5〕 配列番号1の配列、配列番号2の配列及び配列番号3の配列からなる群より選択される配列を含む、NEK6遺伝子の発現を抑制するアンチセンス核酸;
〔6〕 NEK6遺伝子の発現を抑制するアンチセンス核酸を対象に投与することを含む、SMAD2/3タンパク質のリン酸化を阻害する方法;
〔7〕 NEK6遺伝子の発現を抑制するアンチセンス核酸を対象に投与することを含む、線維症を治療する方法;
〔8〕 SMAD2/3タンパク質のリン酸化の阻害に使用するNEK6遺伝子の発現を抑制するアンチセンス核酸;
〔9〕 線維症治療に使用するNEK6遺伝子の発現を抑制するアンチセンス核酸;
〔10〕 SMAD2/3タンパク質のリン酸化阻害剤を製造するための、NEK6遺伝子の発現を抑制するアンチセンス核酸の使用;
〔11〕 線維症治療剤を製造するための、NEK6遺伝子の発現を抑制するアンチセンス核酸の使用;
〔12〕NEK6遺伝子の発現を抑制する核酸が、KB−XAX、KB−XBX又はKB−XCXの配列を含む核酸である、〔11〕の使用;
〔13〕 NEK6遺伝子の発現を抑制する核酸を有効成分として含むSMAD2/3タンパク質のリン酸化阻害剤であって、上記核酸はNEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とするものである、阻害剤;
〔14〕 NEK6遺伝子の発現を抑制する核酸を有効成分として含む線維症治療剤であって、上記核酸はNEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とするものである、治療剤;
〔15〕 線維症が肺線維症、肝線維症又は腎線維症である、〔14〕の治療剤;
〔16〕 NEK6遺伝子の発現を抑制する核酸が、配列番号1の配列と少なくとも90%の配列同一性を有する配列、配列番号2の配列と少なくとも90%の配列同一性を有する配列及び配列番号3の配列と少なくとも90%の配列同一性を有する配列からなる群より選択される配列を含む核酸である、[13]の阻害剤;
〔17〕 NEK6遺伝子の発現を抑制する核酸が、配列番号1の配列、配列番号2の配列及び配列番号3の配列からなる群より選択される配列を含む核酸である、[13]の阻害剤;
〔18〕 NEK6遺伝子の発現を抑制する核酸であって、NEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とする核酸を対象に投与することを含む、SMAD2/3タンパク質のリン酸化を阻害する方法;
〔19〕 NEK6遺伝子の発現を抑制する核酸であって、NEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とする核酸を対象に投与することを含む、線維症を治療する方法;
〔20〕 SMAD2/3タンパク質のリン酸化の阻害に使用する、NEK6遺伝子の発現を抑制する核酸であって、NEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とする核酸;
〔21〕 線維症治療に使用する、NEK6遺伝子の発現を抑制する核酸であって、NEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とする核酸;
〔22〕 SMAD2/3タンパク質のリン酸化阻害剤を製造するための、NEK6遺伝子の発現を抑制する核酸の使用であって、上記核酸はNEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とするものである使用;
〔23〕 線維症治療剤を製造するための、NEK6遺伝子の発現を抑制する核酸の使用であって、上記核酸はNEK6遺伝子のmRNAの3’非翻訳領域上の配列を標的とするものである使用;
〔24〕 NEK6遺伝子の発現を抑制する核酸が、KB−XAX、KB−XBX又はKB−XCXの配列を含む核酸である、〔23〕の使用;
[25] NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、10〜40塩基である、[1]の阻害剤;
〔26〕 NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、12〜21塩基である、[1]の阻害剤;
[27] NEK6遺伝子の発現を抑制するアンチセンス核酸の配列の両端に人工核酸が導入されている、[1]の阻害剤;
[28] NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、12〜21塩基であり、配列の両端に人工核酸が導入されている、[1]の阻害剤;
[29] NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、10〜40塩基である、[2]の治療剤;
〔30〕 NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、12〜21塩基である、[2]の治療剤;
[31] NEK6遺伝子の発現を抑制するアンチセンス核酸の配列の両端に人工核酸が導入されている、[2]の治療剤;
[32] NEK6遺伝子の発現を抑制するアンチセンス核酸に含まれる塩基数が、12〜21塩基であり、配列の両端に人工核酸が導入されている、[2]の治療剤;
[33] アンチセンス核酸が、リポソーム、グリコール酸共重合体(PLGA)マイクロスフェア、リピドマイクロスフェア、高分子ミセル、ゲル剤又はエキソソームのドラッグデリバリーキャリアに封入されて投与される、[32]の治療剤。
NEK6タンパク質は、細胞分裂の制御に関わる11個のNIMA−related serine/threonine kinase familyの1つであり、細胞周期のM期においてリン酸化(活性化)される。
アンチセンス核酸は、標的とするmRNAと配列特異的に二重鎖を形成し、そのスプライシング阻害及び翻訳阻害等の機能阻害を行うオリゴヌクレオチド(アンチセンスDNA及び/又はアンチセンスRNA)であり、標的とするmRNAの全長もしくは一部に対するアンチセンス核酸を細胞内に導入することで効果を発揮する。
1)mRNAの5’キャップ部位から開始コドンの約25塩基下流までの領域を標的配列とする翻訳開始複合体の立体的阻害
2)標的mRNAと相補的な一本鎖DNAであり、RNaseHを介したmRNA分解
3)pre−mRNAのエキソンとイントロンの境界領域を標的配列とするスプライシング阻害(mRNAの成熟阻害)
があげられる。NEK6遺伝子の発現を抑制するものであれば、そのメカニズムは特に制限されるものではない。
〔1〕配列番号1の配列と少なくとも90%の配列同一性を有する配列を含む、核酸。
〔2〕配列番号2の配列と少なくとも90%の配列同一性を有する配列を含む、核酸。
〔3〕配列番号3の配列と少なくとも90%の配列同一性を有する配列を含む、を含む、核酸。
NEK6遺伝子の発現を抑制する核酸の1つであるsiRNA(small interfering RNA)を以下に説明する。
(a)配列番号1の配列と少なくとも90%の配列同一性を有する配列を含むガイド鎖(アンチセンス鎖)と、パッセンジャー鎖(センス鎖)から形成される二本鎖核酸分子
(b)配列番号2の配列と少なくとも90%の配列同一性を有する配列を含むガイド鎖(アンチセンス鎖)と、パッセンジャー鎖(センス鎖)から形成される二本鎖核酸分子
(c)配列番号3の配列と少なくとも90%の配列同一性を有する配列を含むガイド鎖(アンチセンス鎖)と、パッセンジャー鎖(センス鎖)から形成される二本鎖核酸分子
NEK6遺伝子の発現を抑制する核酸の1つとなるssPN分子について説明する。ssPN分子は、WO2012/017919に開示される生物学的安定性に優れた一本鎖RNA核酸分子を意味し、具体的には以下の通りである。
NEK6遺伝子の発現を抑制する核酸の1つであるssNc分子を説明する。
ssNc分子は、標的遺伝子の発現を抑制する発現抑制配列を含む一本鎖核酸分子であって、
5’側から3’側にかけて、5’側領域(Xc)、内部領域(Z)及び3’側領域(Yc)を、上記順序で含み、
上記内部領域(Z)が、内部5’側領域(X)及び内部3’側領域(Y)が連結して構成され、
上記5’側領域(Xc)が、上記内部5’側領域(X)と相補的であり、
上記3’側領域(Yc)が、上記内部3’側領域(Y)と相補的であり、
上記内部領域(Z)、上記5’側領域(Xc)及び上記3’側領域(Yc)の少なくとも一つが、発現抑制配列を含むことを特徴とする。
ssPN分子及びssNc分子の合成方法は、特に制限されず、従来公知の方法が採用できる。上記合成方法は、例えば、遺伝子工学的手法による合成法、化学合成法等があげられる。遺伝子工学的手法は、例えば、インビトロ転写合成法、ベクターを用いる方法、PCRカセットによる方法等があげられる。上記ベクターは、特に制限されず、プラスミド等の非ウイルスベクター、ウイルスベクター等があげられる。上記化学合成法は、特に制限されず、例えば、ホスホロアミダイト法及びH−ホスホネート法等があげられる。上記化学合成法は、例えば、市販の自動核酸合成機を使用可能である。上記化学合成法は、一般に、アミダイトが使用される。上記アミダイトは、特に制限されず、市販のアミダイトとして、例えば、RNA Phosphoramidites(2’−O−TBDMSi、商品名、三千里製薬)、ACEアミダイト、TOMアミダイト、CEEアミダイト、CEMアミダイト、TEMアミダイト等があげられる。また、本発明のssPN分子及びssNc分子は、WO2012/05368、WO2012/17919、WO2013/27843、WO2016/159374に記載の製造方法に従って製造することができる。
NEK6遺伝子の発現を抑制する核酸の1つであるmiRNAについて以下に説明する。
本実施形態において、有効成分である核酸に使用されるヌクレオチド残基は、構成要素として、糖、塩基及びリン酸を含む。上記ヌクレオチド残基は、例えば、リボヌクレオチド残基及びデオキシリボヌクレオチド残基等があげられる。上記リボヌクレオチド残基は、例えば、糖としてリボース残基を有し、塩基として、アデニン(A)、グアニン(G)、シトシン(C)及びウラシル(U)を有し、上記デオキシリボース残基は、例えば、糖としてデオキシリボース残基を有し、塩基として、アデニン(A)、グアニン(G)、シトシン(C)及びチミン(T)を有する。
本実施形態において、有効成分である核酸、リンカー等の説明にて使用される用語は、当該技術分野での通常用いられるものであり、例えば、以下のように示すことができる。
SMAD2/3タンパク質のリン酸化阻害とは、TGF−β刺激により促進されるSMAD2及び/又はSMAD3のリン酸化が阻害(制御)されることを意味する。
本実施形態に係る線維症治療剤は、肝線維症、肝硬変、ウイルス性肝炎、自己免疫性肝炎、原発性胆汁性肝炎、非アルコール性脂肪肝炎、アルコール性肝疾患、原発性硬化性胆菅炎、ヘモクロマトーシス、ウイルソン病、α1−アンチトリプシン欠損症、非ウイルス性鬱血性肝硬変、薬剤性肝障害、膵炎、膵線維症、網膜線維症、声帯瘢痕化、声帯粘膜線維症、喉頭線維症、肺線維症、間質性肺炎、特発性肺線維症、非特異性間質性肺炎、特発性器質化肺炎、剥離性間質性肺炎、呼吸細気管支炎関連間質性肺炎、急性間質性肺炎、リンパ球性間質性肺炎、サルコイドーシス、慢性好酸球性肺炎、急性好酸球性肺炎、リンパ脈管筋腫症、肺胞蛋白症、ヘルマンスキー・パドラック症候群、肺ランゲルハンス細胞組織球症、鉄肺症、アミロイドーシス、肺胞微石症、過敏性肺炎、じん肺、感染性肺疾患、薬剤性肺炎、放射線肺炎、嚢胞性線維症、骨髄線維症、腎線維症、慢性腎不全、糖尿病性腎症、慢性糸球体腎炎、悪性腎硬化症、多発性嚢胞腎、薬剤性腎障害、後腹膜線維症、膠原病、強皮症、先天性角化不全症、腎性全身性線維症の他、気道の線維化、腸管の線維化、膀胱の線維化、前立腺の線維化、皮膚の線維化を含む広く線維化に関する疾患に対する治療剤である。好ましくは、肝線維症、肝硬変、肺線維症、間質性肺炎、腎線維症又は慢性腎不全であり、より好ましくは、肺線維症、肝線維症又は腎線維症である。
ヒト肝星細胞株LI−90細胞に、ヒトNEK6アンチセンスオリゴヌクレオチド(KB−XAX、KB−XBX、KB−XCX)を、Lipofectamine RNAi MAX(Invitrogen社)を用いて、終濃度30nMでトランスフェクションした。トランスフェクション48時間後、培地を10% FCS含有DMEM Low Glucose培地(Thermo Fisher社)から0.2% FCS含有DMEM Low Glucose培地(Thermo Fisher社)に交換した。トランスフェクションから96時間後、アンチセンスオリゴヌクレオチドをトランスフェクションした細胞から、RNeasy Mini Kit(Qiagen社)を用いてRNAを抽出した。
NEK6アンチセンスオリゴヌクレオチド(KB−XAX):5’−GCAATCCTGAAGGTAG−3’(配列番号1)
NEK6アンチセンスオリゴヌクレオチド(KB−XBX):5’−GACAGCTCAGACAATT−3’(配列番号2)
NEK6アンチセンスオリゴヌクレオチド(KB−XCX):5’−TCAAGGAGGTGACGAA−3’(配列番号3)
5’−ATTGGAGGGCAAGTCTGGTGCCAGC−3’(配列番号5)
カスタム合成18s Primer1(ThermoFisher社):
5’−CGGCTACCACATCCAAGGAAG−3’(配列番号6)
カスタム合成18s Primer2(ThermoFisher社):
5’−GCTGGAATTACCGCGGCT−3’(配列番号7)
NEK6アンチセンスオリゴヌクレオチドがTGF−βシグナルを制御する可能性を検討するため、各NEK6アンチセンスオリゴヌクレオチドをトランスフェクションした細胞においてリン酸化SMAD3の量を解析した。
NEK6タンパク質が細胞内でSMAD3と相互作用してSMAD3をリン酸化しているかを検討するため、共免疫沈降を行った。
NEK6タンパク質がSMAD3タンパク質を基質として直接リン酸化している可能性を、NEK6とSMAD3の精製タンパク質を用いて検討した。
NEK6タンパク質が、SMADタンパク質複合体の核内移行後におこる転写活性も制御しているかを検討するため、SMADタンパク質複合体のDNA結合配列とルシフェラーゼ遺伝子を用いたルシフェラーゼレポーターアッセイを実施した。また、同時に調製したLL29細胞を用いてウェスタンブロッティングを実施し、NEK6のノックダウンについて確認した。
siNEK6:5’−CUGUCCUCGGCCUAUCUUC−3’(配列番号9)
siNEK6:5’−UAUUUGGGUGGUUCAGUUG−3’(配列番号10)
siNEK6:5’−CAACUCCAGCACAAUGUUC−3’(配列番号11)
siNEK6:5’−UACUUGAUCAUCUGCGAGA−3’(配列番号12)
NEK6のノックダウンが線維症に対して有効性を示すことを検討するため、NEK6 アンチセンスオリゴヌクレオチドをトランスフェクションした細胞における線維症関連遺伝子の転写量を解析した。
5’−ATTGGAGGGCAAGTCTGGTGCCAGC−3’(配列番号5)
カスタム合成18s Primer1(ThermoFisher社):
5’−CGGCTACCACATCCAAGGAAG−3’(配列番号6)
カスタム合成18s Primer2(ThermoFisher社):
5’−GCTGGAATTACCGCGGCT−3’(配列番号7)
NEK6のノックダウンが線維症に対して有効性を示すことをさらに検討するため、NEK6 siRNAをトランスフェクションした細胞における線維症関連遺伝子の転写量を解析した。
NEK6タンパク質がTGF−βシグナルを制御する可能性を検討するため、NEK6 siRNAをトランスフェクションした細胞においてリン酸化SMAD3の量を解析した。
NEK6のノックダウンが線維症に対して有効性を示すことを確認するため、CCl4モデルマウスに、NEK6 siRNAを静脈内投与して抗線維化作用を解析した。
線維化とは、細胞や組織の障害に対する過剰な創傷治癒過程だと理解されている。そのため、線維化と共に細胞や組織の障害を抑制することは、各種線維症の治療に有効であると考えられている。そこで、NEK6のノックダウンが肝障害に対して効果を示すかを検討するため、CCl4モデルにおける肝障害マーカーの測定を行った。
NEK6のノックダウンがSMAD3タンパク質のリン酸化に対して効果を示すかを検討するため、CCl4モデルにおけるリン酸化SMAD3の量を解析した。
NEK6のノックダウンが線維化に対して有効性を示すかを検討するため、CCl4モデルにおける線維症関連遺伝子の転写量を解析した。
NEK6のノックダウンが線維症に対して有効性を示すことを検討するため、胆管結紮誘発肝線維化モデルマウス(BDLモデル)にNEK6 siRNAを静脈内投与して線維症関連遺伝子の転写量を解析した。
NEK6のノックダウンがCCl4誘発肝線維化モデルに対して効果を示すかを検討するため、病理像の観察を行った。
以下に示す核酸分子を、ホスホロアミダイト法に基づき、核酸合成機(商品名ABI3900 DNA Synthesizer、Applied Biosystems)により合成した。固相担体としてCPG(Controlled Pore Glass)を用い、RNAアミダイトとして、EMMアミダイト(国際公開第2013/027843号)を用いた固相合成を行った。固相担体からの切り出し及びリン酸基保護基の脱保護、塩基保護基の脱保護、2’−水酸基保護基の脱保護は、定法に従った。合成した一本鎖核酸分子は、HPLCにより精製した。
KB−001
5’−GAGGGAGUUCCAACAACCUCUCC−Lx−GGAGAGGUUGUUGGAACUCCCUCCA−3’(配列番号13)
KB−002
5’−CGAGGCAGGACUGUGUCAAGGCC−Lx−GGCCUUGACACAGUCCUGCCUCGCC−3’(配列番号14)
KB−003
5’−CGUGGAGCACAUGCAUUCACGCC−Lx−GGCGUGAAUGCAUGUGCUCCACGGC−3’(配列番号15)
KB−004
5’−GAUAAGAUGAAUCUCUUCUCCCC−Lx−GGGGAGAAGAGAUUCAUCUUAUCUC−3’(配列番号16)
KB−005
5’−CAGAGACCUGACAUCGGAUACCC−Lx−GGGUAUCCGAUGUCAGGUCUCUGGU−3’(配列番号17)
Claims (5)
- NEK6遺伝子の発現を抑制するアンチセンス核酸を有効成分として含むSMAD2/3タンパク質のリン酸化阻害剤。
- NEK6遺伝子の発現を抑制するアンチセンス核酸を有効成分として含む線維症治療剤。
- 線維症が肺線維症、肝線維症又は腎線維症である、請求項2の治療剤。
- NEK6遺伝子の発現を抑制するアンチセンス核酸が、配列番号1の配列と少なくとも90%の配列同一性を有する配列、配列番号2の配列と少なくとも90%の配列同一性を有する配列及び配列番号3の配列と少なくとも90%の配列同一性を有する配列からなる群より選択される配列を含む、請求項1記載の阻害剤。
- NEK6遺伝子の発現を抑制するアンチセンス核酸が、配列番号1の配列、配列番号2の配列及び配列番号3の配列からなる群より選択される配列を含む、請求項1記載の阻害剤。
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US20040097441A1 (en) * | 2002-11-16 | 2004-05-20 | Isis Pharmaceuticals Inc. | Modulation of NIMA-related kinase 6 expression |
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US3687808A (en) | 1969-08-14 | 1972-08-29 | Univ Leland Stanford Junior | Synthetic polynucleotides |
WO2012005368A1 (ja) | 2010-07-08 | 2012-01-12 | 株式会社ボナック | 遺伝子発現制御のための一本鎖核酸分子 |
DK2674494T3 (en) | 2010-08-03 | 2015-02-23 | Bonac Corp | Single-stranded RNA molecule with a nitrogen-containing alicyclic skeleton |
EP2749565B1 (en) | 2011-08-25 | 2017-05-31 | Bonac Corporation | Nucleoside phosphoramidates for producing nucleic acids |
WO2016159374A1 (ja) | 2015-04-02 | 2016-10-06 | 株式会社ボナック | 配糖体化合物の製造方法 |
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US20040097441A1 (en) * | 2002-11-16 | 2004-05-20 | Isis Pharmaceuticals Inc. | Modulation of NIMA-related kinase 6 expression |
WO2019022257A1 (ja) * | 2017-07-28 | 2019-01-31 | 杏林製薬株式会社 | 線維症治療剤 |
Non-Patent Citations (5)
Title |
---|
BMB REPORTS, vol. 48, no. 8, JPN6019012722, 2015, pages 473 - 478, ISSN: 0004989137 * |
CANCER LETTERS, vol. 335, no. 1, JPN6019012717, 2013, pages 175 - 182, ISSN: 0004989135 * |
CANCER RESEACH, vol. 77, no. 3, JPN6019012715, 2017, pages 753 - 765, ISSN: 0004989136 * |
PLOS ONE, vol. 9, no. 4, JPN6019012720, 2014, pages 96095 - 1, ISSN: 0004915701 * |
SCIENTIFIC REPORTS, vol. Vol. 8, No. 1, 16047, JPN6019012718, 2018, ISSN: 0004989138 * |
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