JP2019528056A - ポンペ病用アンチセンスオリゴマー化合物 - Google Patents
ポンペ病用アンチセンスオリゴマー化合物 Download PDFInfo
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Abstract
Description
本発明は、ポンペ病の治療に有用なアンチセンスオリゴヌクレオチド及びアンチセンスオリゴヌクレオチドを含む医薬組成物に関する。本発明はまた、GAA遺伝子のプレmRNAのスプライシングをモジュレートする方法及びポンペ病の治療に関する。
酸性マルターゼ欠損症又はII型グリコーゲン貯蔵病としても知られるポンペ病は、体全体にわたり筋肉及び神経細胞に損傷を与える常染色体劣性代謝障害である。それはリソソーム酸性α−グルコシダーゼ酵素の欠損に起因してリソソームにグリコーゲンが蓄積することにより引き起こされる。グリコーゲンが蓄積すると体全体にわたり進行性筋力低下(筋症)が起こり、各種生体組織、とくに心臓、骨格筋、肝臓、及び神経系が影響を受ける。
一態様では、本発明は、GAA遺伝子のc546G>T突然変異に起因して使用される天然潜在スプライス部位の周りの領域、より特定的には配列番号1の配列、より特定的には配列番号2〜90から選択される配列、さらにより特定的には配列番号2及び5〜23から選択される配列を標的とするアンチセンスオリゴマー化合物を含む。
アンチセンス技術を裏付ける原理は、標的核酸にハイブリダイズするアンチセンス化合物が転写、スプライシング、翻訳などの遺伝子発現活性をモジュレートすることにある。こうした配列特異性のおかげで、アンチセンス化合物は、標的検証及び遺伝子機能付与のツールとしてさらには疾患に関与する遺伝子発現又は遺伝子産物を選択的にモジュレートする治療剤としてきわめて魅力的なものとなる。
細胞培養、シクロヘキシミド処理、及びAONトランスフェクション
皮膚生検により初代線維芽細胞を取得し、5%CO2中37℃で10%FBS(Hyclone)及びペニシリン/ストレプトマイシン/グルタミン(Gibco)を含む高グルコース(Lonza)DMEM中で培養した。48時間にわたり100μg/mlシクロヘキシミド(Sigma)の濃度でシクロヘキシミド処理を行った。AONのトランスフェクションは、4.5μlエンドポーター試薬(Gene Tools)/ml培地を用いて実施した。ホスホロジアミデートモルホリノオリゴマー骨格を有するAON(Gene Tools)を20μMでトランスフェクトした。
すでに記載されているようにmRNA分析を実施した(Bergsma, et al., 2015)。簡単に言えば、RNAを採取し、製造業者のプロトコルに従ってRNAeasyミニプレップキット(Qiagen)を用いて精製した。製造業者の取扱い説明書に従ってiScript(Biorad)を用いて800ngのRNAに対してcDNA合成を実施した。さらなる分析の前にcDNAを5倍希釈した。FastStart Taqポリメラーゼ(Roche)を用いてサンプルに対してRT−PCRを実施した。BigDye Terminator v3.1(Thermo)を用いてPCRサンプルに対して配列解析を直接実施した。産物が非常に低レベルで存在した場合、TOPO(登録商標)TA Cloning Kit (Thermo)を用いてTOPOクローニングを実施した。ITaq universal SYBR Green Supermix (Biorad)を用いてRT−qPCRを行った。β−アクチンをRT−qPCR分析用の内部対照として使用した。使用したプライマーはすべて、表A及びBに示される。
5つのアルゴリズム、即ち、SpliceSiteFinder-like (SSF)、MaxEntScan (MES)、NNSplice (NNS)、GeneSplicer (GS)、及びHuman Splicing Finder (HSF)を適用するAlamut Visual v. 2.4.2 (Interactive Biosoftware)を用いてスプライシング予測を実施した。設定は、Molecular Diagnostics at the Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands and are published in Bergsma et al., 2015で標準的診断に使用されるものと同一であった。5つのアルゴリズムで異なる最大スコアが使用される。比較のために、最大スコアを基準にした%としてスコアを計算した。2つ以上のアルゴリズムで≧10%の変化を有意な閾値として使用した。200ベースのウィンドウ範囲を用いて相対スプライス部位強度も予測した(Mucaki et al., 2013)を有するASSEDA (http://splice.uwo.ca/; version August 2014)。
Molecular Diagnostics at the Department of Clinical Genetics, Erasmus MC, Rotterdam, The NetherlandsでゲノムDNA変異体を同定した。Big Dye Terminator kit v3.1 (Applied Biosystems)を用いてフランキングエクソンPCR産物のダイレクトシーケンシングを実施した。純粋DNAサンプルを取得するために、ゲル上に見えるPCR産物を20μlピペットチップで突き刺し、チップ上のDNAを10μl H2Oに再懸濁させた。単一鋳型由来のDNAを取得するために、続いて1μlアリコートを新しいPCR(以上に記載の通り)で使用した。製造業者のプロトコルに従ってFastAP Thermosensitive Alkaline Phosphatase (Thermo Scientific)を用いて過剰のプライマー及びdNTPを除去した。セファデックスG-50 (GE Healthcare)を用いてサンプルを精製し、AB3130 Genetic Analyzer (Applied Biosystems, Hitachi)で配列を決定した。
標準溶解緩衝液(50mMトリス(pH7.5)、100mM NaCl、50mM NaF、1%Tx−100、プロテアーゼ阻害剤)中で細胞を溶解させた。BCA Protein Assay (Thermo)を用いてタンパク質定量を行った。すでに記載されているように(Kroos, et al., 2007)、GAA酵素活性を測定するために4−メチルウンベリフェロン(4−MU)−α−D−グルコピラノシドアッセイを実施した。
Bergsma AJ,Kroos M,Hoogeveen−Westerveld M,Halley D,van der Ploeg AT,Pijnappel WW.2015.Identification and characterization of aberrant GAA pre−mRNA splicing in pompe disease using a generic approach.Hum Mutat 36(1):57−68.
Gort L,Coll MJ,Chabas A.2007.Glycogen storage disease type II in Spanish patients:High frequency of c.1076−1G>C mutation.Mol Genet Metab 92:183−187.
Hermans MP,van Leenen D,Kroos MA,Beesley CE,Van der Ploeg AT,SakurabaH,Wevers R,Kleijer W,MichelakakisH,Kirk EP,Fletcher J,Bosshard N,Basel−Vanagaite L,Besley G,Reuser AJJ.2004.Twento−Two Novel Mutations in the Lysosomal α−Glucosidase Gene(GAA)Underscore the Genotype−Phenotype Correlation in Glycogen Storage Disease Type II.Human Mutat 23:47−56.
Kroos MA,Pomponio RJ,Hagemans ML,Keulemans JL,Phipps M,DeRiso M,Palmer RE,Ausems MG,Van der Beek NA,Van Diggelen OP and others.2007.Broad spectrum of Pompe disease in patients with the same c.−32−13T−>GHaplotype.Neurology 68(2):110−5.
Maimaiti M,Takahashi S,Okajima K,Suzuki N,Ohinata J,Araki A,TanakaH,Mukai T,Fujieda K.2009.Silent exonic mutation in the acid−alpha−glycosidase gene that causes glycogen storage disease type II by affecting mRNA splicing.JHum Genet 54(8):493−6.
Claims (12)
- c546G>T突然変異に対する天然潜在スプライス部位の近傍の領域を標的とするアンチセンスオリゴマー化合物であって、前記潜在スプライスがGAA遺伝子のc.546+184に位置し、より特定的には配列番号1を標的とし、より特定的には配列番号2〜90から選択される配列を標的とし、さらにより特定的には配列番号2及び5〜23から選択される配列を標的とするアンチセンスオリゴマー化合物。
- 配列番号1に結合可能である、請求項1に記載のアンチセンスオリゴマー化合物。
- 非天然化学骨格、好ましくは、ホスホルアミデート、ホスホロジアミデート、モルホリノ、ペプチド、ロックド核酸(LNA)、ホスホロチオエートオリゴマー、トリシクロ−DNA、トリシクロ−ホスホロチオエート、2’O−Me−ホスホロチオエート、又はそれらの任意の組合せからなる群から選択されるものを含む、請求項1又は2に記載のアンチセンスオリゴマー化合物。
- 10から40ヌクレオチド又はヌクレオチドアナログを含む、請求項1〜3のいずれか一項に記載のアンチセンスオリゴマー化合物。
- 前記アンチセンスオリゴマー化合物が、配列番号91〜179からなる群から選択される配列を有し、任意のチミン(T)残基がウラシル(U)と交換されていてもよく、より特定的には前記配列が配列番号91〜111から選択される、請求項1〜4のいずれか一項に記載のアンチセンスオリゴマー化合物。
- 配列番号91〜179に対して少なくとも80%の同一性を有し、より特定的には前記配列が配列番号91〜111から選択される、請求項1〜4のいずれか一項に記載のアンチセンスオリゴマー化合物。
- 前記オリゴマー化合物が、配列番号91〜179からなる群から選択される配列のヌクレオチドアナログを含み、より特定的には前記配列が配列番号91〜111から選択される、請求項1〜6のいずれか一項に記載のアンチセンスオリゴマー化合物。
- ポンペ病、より特定的には患者がc.546突然変異を有するポンペ病の治療に使用するための、請求項1〜7のいずれか一項に記載のアンチセンスオリゴマー化合物。
- 請求項1〜7のいずれか一項に記載のアンチセンスオリゴマー化合物と薬学的に許容可能な担体とを含む医薬組成物。
- 送達剤をさらに含む、請求項9に記載の医薬組成物。
- GAA遺伝子の核酸配列、特定的には配列番号1に結合可能な化合物、より好ましくは配列番号2〜90の配列のいずれかに結合可能な化合物。
- ポンペ病の患者、より特定的には患者がc.546突然変異を有するポンペ病の患者の治療方法であって、請求項1〜8のいずれか一項に記載のアンチセンスオリゴマー化合物又は請求項9若しくは10に記載の医薬組成物の投与を含む、治療方法。
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