JP2022518430A - Dkk1遺伝子を標的にする二本鎖オリゴヌクレオチド、これを含む構造体及びこれを含む脱毛予防又は発毛用組成物 - Google Patents
Dkk1遺伝子を標的にする二本鎖オリゴヌクレオチド、これを含む構造体及びこれを含む脱毛予防又は発毛用組成物 Download PDFInfo
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Abstract
Description
A-X-R-Y-B 構造式(1)
前記構造式(1)で、Aは親水性物質、Bは疎水性物質、X及びYはそれぞれ独立して、単純共有結合又はリンカー媒介共有結合を意味し、Rは、配列番号72、80、81、209、214、215、216、217、254及び256からなる群から選ばれるいずれか一つの配列を含むセンス鎖及びこれに相補的な配列を含むアンチセンス鎖を含むDKK1特異的二本鎖オリゴヌクレオチドを意味する。
A-X-R-Y-B 構造式(1)
前記構造式(1)で、Aは親水性物質、Bは疎水性物質、X及びYはそれぞれ独立して、単純共有結合又はリンカー媒介の共有結合を意味し、Rは、上記のDKK1特異的二本鎖オリゴヌクレオチドを意味する。一部の態様として、Rは、配列番号72、80、81、209、214、215、216、217、254及び256からなる群から選ばれるいずれか一つの配列を含むセンス鎖及びこれに相補的配列を含むアンチセンス鎖からなるDKK1特異的オリゴヌクレオチドを意味する。
(A’m-J)n 構造式(5)
(J-A’m)n 構造式(6)
前記構造式(5)で、A’は親水性物質単量体(monomer)、Jはm個の親水性物質単量体間、又はm個の親水性物質単量体とsiRNAを互いに連結するリンカー、mは1~15の整数、nは1~10の整数を意味し、(A’m-J)又は(J-A’m)で表される反復単位が、親水性物質ブロックの基本単位に該当する。
(A’m-J)n-X-R-Y-B 構造式(7)
(J-A’m)n-X-R-Y-B 構造式(8)
前記構造式(7)及び構造式(8)で、X、R、Y及びBは、構造式(1)における定義と同一であり、A’、J、m及びnは、構造式(5)及び構造式(6)における定義と同一である。
P-J1-J2-A-X-R-Y-B 構造式(9)
前記構造式(9)で、A、B、R、X及びYは、構造式(1)における定義と同一であり、Pは、アミン基又はポリヒスチジン基を意味し、J1とJ2はリンカーであって、J1は及びJ2は、独立して、単純共有結合、PO3 -、SO3、CO2、C2-12アルキル、アルケニル、アルキニルから選ばれてよいが、これに限定されるものではなく、使用される親水性物質によって本発明の目的に符合するJ1とJ2はいかなるリンカーも使用可能であることは、通常の技術者には明らかである。
P-J1-J2-(A’m-J)n-X-R-Y-B 構造式(10)
P-J1-J2-(J-A’m)n-X-R-Y-B 構造式(11)
前記構造式(10)及び構造式(11)で、X、R、Y、B、A’、J、m及びnは、構造式(5)又は構造式(6)における定義と同一であり、P、J1及びJ2は、構造式(9)における定義と同一である。
(Li-Z)-A-X-R-Y-B 構造式(15)
前記構造式(15)で、A、B、X及びYは、前記構造式(1)における定義と同一であり、Lは、受容体媒介エンドサイトーシス(receptor-mediated endocytosis,RME)によりターゲット細胞内在化(internalization)を増進させる受容体と特異的に結合する特性を有するリガンドを意味し、iは1~5の整数、好ましくは1~3の整数である。
DKK1(Homo sapiens)遺伝子のmRNA配列(NM_012242.3,1913bp)に結合可能な目標塩基配列(センス鎖)を312種デザインした。
実施例1で合成されたヒトDKK1配列を標的にする312種のsiRNAを用いて、DKK1 mRNA発現を効果的に抑制する配列の発掘のためのスクリーニングを行った。
ヒトDKK1発現を効率的に抑制するsiRNA配列の発掘のために、ヒト由来肺癌細胞株であるA549及びヒト毛乳頭細胞であるHFDPCを用いた。A549細胞株は、10%ウシ胎児血清(Hyclone,US)及び1%ペニシリン-ストレプトアビジン(Hyclone,US)が含まれたRPMI培地(Hyclone,US)を用いて37℃、5%CO2条件で培養し、HFDPC細胞株は、SupplementMix(Promo cell,Germany)が含まれた毛乳頭細胞増殖培地(Follicle Dermal Papilla Cell Growth Media)(Promo cell,Germany)を用いて37℃、5%CO2条件で培養した。A549及びHFDPC細胞を12ウェルプレート(Falcon,US)に4×104cells/wellの条件で分注し、翌日、リポフェクタミン(Lipofectamine)RNAiMAX(Invitrogen,US)を用いて、メーカーのプロトコルにしたがってsiRNAを20nMでトランスフェクションさせた。
実施例2-1の方法でA549細胞に312種のsiRNAを3回反復してトランスフェクションした。ユニバーサルRNA抽出キット(Universal RNA extraction kit)(Bioneer)を用いて細胞溶解物から総RNAを抽出し、このRNAを鋳型にしてAccuPower(登録商標) GreenStarTMMaster Mix(Bioneer)を用いて、メーカーのプロトコルにしたがってhDKK1及びhRPL13A(internal control)のmRNA発現レベルを、対照群サンプル対比でhDKK1遺伝子の相対的発現率を分析した。各遺伝子に対するプライマー配列は、下記の通りである(表4)。
実施例2-2で選別された18種のhDKK1 siRNA配列のうち、抑制能の高い10個の配列を対象に、再現性評価のために、A549細胞に10種のsiRNAを3回反復してトランスフェクションした。その結果、1次及び2次のスクリーニングと同様に、10種の配列のいずれも55%以上の阻害能を示し、特に、#72配列では70%以上の高い抑制能を示した(図3及び図4)。
3-1:SAMiRNA-DKK1 #72構造体合成
本発明で製造された二本鎖オリゴヌクレオチド構造体(SAMiRNA)は、下記構造式のような構造を有する。
実施例3-1で合成されたSAMiRNA-DKK1 #72の粒度分析のために、Zetasizer Nano ZS(Malvern,UK)を用いてSAMiRNAのサイズ及び多分散指数(polydispersity index)を測定した結果、SAMiRNA-DKK1 #72に対するナノ粒子のサイズ及び多分散指数は下記表6の通りであり、代表的なグラフは、図6のように測定された。
最終候補物質SAMiRNA-DKK1 #72のDKK1発現抑制効能を評価するために、ヒト毛乳頭細胞であるHFDPCを利用し、HFDPC細胞株は、SupplementMix(Promo cell,Germany)が含まれた毛乳頭細胞増殖培地(Promo cell,Germany)を用いて37℃、5%CO2条件で培養した。HFDPC細胞を12ウェルプレート(Falcon,US)に4×104cells/wellの条件で分注し、翌日、SAMiRNA-DKK1 #72を1X DPBSで希釈して細胞に5μMとなるように処理した。SAMiRNA-DKK1 #72の処理は、12時間ごとに1回ずつ処理する条件で総2回又は4回処理し、37℃、5%CO2条件で培養した。
最終候補物質SAMiRNA-DKK1 #72のDKK1遺伝子発現抑制効果を評価するために、qRT-PCR分析を行った。12ウェルプレート(Falcon,US)に、HFDPC細胞株を4×104cells/wellで分注した後、37℃、5%CO2条件で培養した。翌日、SAMiRNA-DKK1 #72を5μM濃度で2回、4回処理し、陽性対照群は、リポフェクタミンRNAiMAX(Invitrogen,US)を用いてSAMiRNA-DKK1 #72を20nMでトランスフェクションした。48時間培養後、ユニバーサルRNA抽出キット(Bioneer,KR)を用いて細胞溶解物から総RNAを抽出し、このRNAを鋳型にしてAccuPower(登録商標) GreenStarTMMaster Mix(Bioneer,KR)を用いてメーカーのプロトコルにしたがってDKK1及びRPL13A(internal control)のmRNA発現レベルをqRT-PCRで分析した。
最終候補物質SAMiRNA-DKK1 #72を用いてHFDPC細胞株でDKK1タンパク質の発現抑制効果を確認した。12ウェルプレート(Falcon,US)にHFDPC細胞株を4×104cells/wellで分注した後、37℃、5%CO2条件で培養し、翌日、SAMiRNAを5μM濃度で2回、4回処理した。陽性対照群は、リポフェクタミンRNAiMAX(Invitrogen,US)を用いてSAMiRNAを20nMでトランスフェクションした。48時間培養後、上澄液を集めてサンプリングし、ヒトDkk-1 Quantikine ELISAキット(R&D systems,US)を用いてメーカーのプロトコルにしたがってDKK1タンパク質の発現量を定量的に分析した。
最終選別されたSAMiRNA-DKK1 #72のヒトの毛根内伝達効率を確認するために、ヒトの毛髪を対象に伝達効果を確認した。毛髪は、実験当日に髪の毛の先端部分を取って抜いて採取し、毛根から1cm程度に切った後、96ウェルプレートに200ul M199培地(10%FBS+1%ペニシリン)に1時間培養した。その後、FAM蛍光物質が標識されたSAMiRNA 10uMが含まれているM199培地200ulに24時間培養した。SAMiRNAを24時間処理し、DPBSを用いて3回の洗浄後に、最終的に3.7%ホルムアルデヒド、2%FBSが含まれているPBSで20分間毛根固定作業を行った。固定の完了した毛根を、OCT化合物(OCT compound)が入っているベースモールド(base mold)に植え、あらかじめ凍らせておいたステンレスプレート上に乗せてOCT化合物を完全に凍らせた。凍らせた組織は-70℃に保管し、組織切片器で切る前に、組織切片がし易くなるように-20℃に30分程度置いた。切片組織は、10um厚でスライドに乗せて1時間乾燥させ、乾燥が終わると、DAPI含有のマウンティングメディアムを用いてマウント過程を行った。
Claims (33)
- 配列番号72、80、81、209、214、215、216、217、254及び256からなる群から選ばれるいずれか一つの配列を含むセンス鎖(sense strand)及びこれに相補的な配列を含むアンチセンス鎖(anti-sense strand)を含むDKK1特異的二本鎖オリゴヌクレオチド。
- 前記センス鎖又はアンチセンス鎖は、19~31個のヌクレオチドで構成されることを特徴とする、請求項1に記載のDKK1特異的二本鎖オリゴヌクレオチド。
- 前記オリゴヌクレオチドは、siRNA、shRNA又はmiRNAであることを特徴とする、請求項1に記載のDKK1特異的二本鎖オリゴヌクレオチド。
- 前記センス又はアンチセンス鎖はそれぞれ独立してDNA又はRNAであることを特徴とする、請求項1に記載のDKK1特異的二本鎖オリゴヌクレオチド。
- 前記二本鎖オリゴヌクレオチドのセンス鎖又はアンチセンス鎖は、化学的修飾(chemical modification)を含むことを特徴とする、請求項1に記載のDKK1特異的二本鎖オリゴヌクレオチド。
- 前記化学的修飾は、ヌクレオチド内の糖(sugar)構造の2’炭素位置において水酸化基(-OH)がメチル基(-CH3)、メトキシ基(-OCH3)、アミン基(-NH2)、フッ素(-F)、O-2-メトキシエチル基、O-プロピル基、O-2-メチルチオエチル基、O-3-アミノプロピル基、O-3-ジメチルアミノプロピル基、O-N-メチルアセトアミド基及びO-ジメチルアミドオキシエチルからなる群から選ばれるいずれか一つに置換される修飾;
ヌクレオチド内の糖構造の酸素が硫黄に置換される修飾;
ヌクレオチド結合がホスホロチオエート(phosphorothioate)結合、ボラノホスフェート(boranophosphate)結合及びメチルホスフェート(methyl phosphonate)結合からなる群から選ばれるいずれか一つの結合となる修飾;及び
PNA(peptide nucleic acid)、LNA(locked nucleic acid)及びUNA(unlocked nucleic acid)形態への修飾;からなる群から選ばれるいずれか一つ以上であることを特徴とする、請求項5に記載のDKK1特異的二本鎖オリゴヌクレオチド。 - 前記二本鎖オリゴヌクレオチドのアンチセンス鎖の5’末端に、一つ以上のリン酸基(phosphate group)が結合していることを特徴とする、請求項1に記載のDKK1特異的二本鎖オリゴヌクレオチド。
- 下記構造式(1)で表される構造を含む、DKK1特異的二本鎖オリゴヌクレオチド構造体:
A-X-R-Y-B 構造式(1)
前記構造式(1)で、Aは親水性物質、Bは疎水性物質、X及びYはそれぞれ独立して、単純共有結合又はリンカー媒介の共有結合を意味し、Rは、請求項1~7のいずれか一項に記載の二本鎖オリゴヌクレオチドを意味する。 - 前記親水性物質は、ポリエチレングリコール(PEG)、ポリビニルピロリドン及びポリオキサゾリンからなる群から選ばれる、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記親水性物質は、下記構造式(5)又は構造式(6)で表される構造を有することを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体:
(A’m-J)n 構造式(5)
(J-A’m)n 構造式(6)
前記構造式(5)又は構造式(6)で、A’は親水性物質単量体(monomer)を、Jは、m個の親水性物質単量体間、又はm個の親水性物質単量体と二本鎖オリゴヌクレオチドとを互いに連結するリンカーを、mは1~15の整数、nは1~10の整数を意味し、
親水性物質単量体A’は、下記化合物(1)~化合物(3)から選ばれたいずれか1つの化合物であり、リンカー(J)は、-PO3 --、-SO3-及び-CO2-からなる群から選ばれる;
- 下記構造式(7)又は構造式(8)で表される構造を有することを特徴とする、請求項12に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体:
(A’m-J)n-X-R-Y-B 構造式(7)
(J-A’m)n-X-R-Y-B 構造式(8)。 - 前記親水性物質の分子量は、200~10,000であることを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記疎水性物質の分子量は、250~1,000であることを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記疎水性物質は、ステロイド誘導体、グリセリド誘導体、グリセロールエーテル、ポリプロピレングリコール、C12~C50の不飽和又は飽和炭化水素、ジアシルホスファチジルコリン(diacylphosphatidylcholine)、脂肪酸、リン脂質、リポポリアミン(lipopolyamine)、脂質(lipid)、トコフェロール(tocopherol)及びトコトリエノール(tocotrienol)からなる群から選ばれるいずれか一つであることを特徴とする、請求項15に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記ステロイド誘導体は、コレステロール、コレスタノール、コール酸、ギ酸コレステロール、ギ酸コレスタニル及びコレステリルアミンからなる群から選ばれるいずれか一つであることを特徴とする、請求項16に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記グリセリド誘導体は、モノ-グリセリド、ジ-グリセリド及びトリ-グリセリドからなる群から選ばれるいずれか一つであることを特徴とする、請求項16に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記X及びYで表される共有結合は、非分解性結合又は分解性結合であることを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記非分解性結合は、アミド結合又はリン酸結合であることを特徴とする、請求項19に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記分解性結合は、ジスルフィド結合、酸分解性結合、エステル結合、アンハイドライド結合、生分解性結合及び酵素分解性結合からなる群から選ばれるいずれか一つであることを特徴とする、請求項19に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記親水性物質に受容体媒介エンドサイトーシス(receptor-mediated endocytosis,RME)によってターゲット細胞内在化(internalization)を増進させる受容体と特異的に結合する特性を有するリガンド(ligand)がさらに結合したことを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記リガンドは、ターゲット受容体特異的抗体、アプタマー、ペプチド、葉酸(folate)、N-アセチルガラクトサミン(N-acetyl Galactosamine,NAG)、ブドウ糖(glucose)及びマンノース(mannose)からなる群から選ばれることを特徴とする、請求項22に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記親水性物質のsiRNAと結合した反対側末端部位に、アミン基又はポリヒスチジン(polyhistidine)基がさらに導入されたことを特徴とする、請求項8に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記アミン基又はポリヒスチジン(polyhistidine)基は、1つ以上のリンカーを介して親水性物質又は親水性ブロックと連結されたことを特徴とする、請求項24に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 前記ポリヒスチジン(polyhistidine)基は、3~10個のヒスチジンを含むことを特徴とする、請求項24に記載のDKK1特異的二本鎖オリゴヌクレオチド構造体。
- 請求項8~26のいずれか一項に記載の二本鎖オリゴヌクレオチド構造体を含むナノ粒子(nanoparticle)。
- 前記ナノ粒子は、異なる配列を有する二本鎖オリゴヌクレオチドを含む二本鎖オリゴヌクレオチド構造体が混合して構成されることを特徴とする、請求項27に記載のナノ粒子。
- 前記ナノ粒子は、凍結乾燥した形態であることを特徴とする、請求項27に記載のナノ粒子。
- 請求項8~26のいずれか一項に記載の二本鎖オリゴヌクレオチド構造体を有効成分として含む脱毛予防又は発毛促進用医薬組成物。
- 請求項27に記載のナノ粒子を有効成分として含む脱毛予防又は発毛促進用医薬組成物。
- 請求項8~26のいずれか一項に記載の二本鎖オリゴヌクレオチド構造体を有効成分として含む脱毛予防又は発毛促進用化粧料組成物。
- 請求項27に記載のナノ粒子を有効成分として含む脱毛予防又は発毛促進用化粧料組成物。
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