JP2015518872A - アロステリックシャペロンおよびその使用 - Google Patents
アロステリックシャペロンおよびその使用 Download PDFInfo
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- JP2015518872A JP2015518872A JP2015515527A JP2015515527A JP2015518872A JP 2015518872 A JP2015518872 A JP 2015518872A JP 2015515527 A JP2015515527 A JP 2015515527A JP 2015515527 A JP2015515527 A JP 2015515527A JP 2015518872 A JP2015518872 A JP 2015518872A
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- gaa
- chaperone
- nac
- glucosidase
- lysosomal
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Abstract
Description
a)第一の治療薬の治療有効量を含む第1の医薬組成物を提供すること、及び
b)患者の心膜腔へ第1の医薬組成物を投与すること
を含む冠状症状の治療または予防の方法を開示している。第一の治療剤は、NFkBの阻害剤としての活性より、NAC金属キレート剤および抗酸化剤であってもよい。
a)フルオロフォアでNACおよび/またはNASおよび/またはNAGシャペロンをラベルする工程;
b)ある量のrhGAAを該標識されたNACおよび/またはNASおよび/またはNAGに添加して基礎的なrhGAAの蛍光を得る工程;
c)基礎的なrhGAAの蛍光を測定する工程;
d)試験剤を添加する工程;
e)rhGAAの蛍光を測定する工程;
f)(c)およびe)で測定したrhGAAの蛍光を比較する工程;
を含み、
ここで、蛍光の強度の変化や蛍光の波長の変化が観察された場合には、試験薬剤は、GAAのためのアロステリック非阻害性シャペロンである、
GAAためのアロステリック非阻害性シャペロンを同定するための方法である。
線維芽細胞培
PDおよびファブリー病患者由来の線維芽細胞は、患者のインフォームドコンセントを得た後、皮膚生検から得た。年齢をマッチさせたノーマル対照線維芽細胞は、、ナポリのフェデリコII大学の小児科研究室で入手可能であった。全ての細胞株は、100 U/mlペニシリンおよび100mg/mlストレプトマイシンを添加したダルベッコ改変イーグル培地(Invitrogen社、グランドアイランド、NY)および10%ウシ胎児血清(シグマアルドリッチ、セントルイス、MO)、5%CO2、37℃で増殖させた。
rhGAAの(alglucosidase、Myozyme)とrh-α-Gal A(アガルシダーゼ-β、Fabrazyme)はジェンザイム社(ケンブリッジ、マサチューセッツ州、米国)からのものであった。酵素は、NAC、NAS、NAG、Cys、Ser、Gly、2-メルカプトエタノール、4-ニトロフェニル-a-グルコピラノシド(4NP-GLC)に製造業者の指示従って調製し、希釈し、NB-DNJとDGJはシグマアルドリッチから購入した。
[フラナガンら2009]に記載されているようにrhGAAの熱安定性スキャンを行った。簡単に説明すると、酵素2.5μgを、それぞれ、10mMのおよび0.1mMのNACおよびDNJの不在および存在下で、SYPROオレンジ染料、およびリン酸ナトリウム25mM緩衝液、pH7.4の150mMのNaCl、または酢酸ナトリウム25mM緩衝液、pH5.2の150mMのNaCl、でインキュベートした。熱安定性スキャンは、リアルタイムライトサイクラー(Bio-Rad)で範囲25〜95°Cにおいて1℃/分で行った。SYPROオレンジ蛍光は、相対的な蛍光を得るために、各スキャン内で最大蛍光値に対して正規化した。融解温度は、(ニーセンら、2007)に従って計算した。
rhGAAの標準活性アッセイは、pH4.0の100mM酢酸ナトリウムおよび20mMの4NP-Glcにおいて、37℃で酵素5μgを用いて、200μlで行った。反応は、酵素を添加することによって開始した。適切なインキュベーション時間(1〜2分)後に反応物をpH10.2の1M炭酸ナトリウムの800 μlを添加することによりブロックした。吸光度は、室温で420nmで測定し、酵素単位を算出する吸光係数は17.2mM-1cm-1であった。一酵素単位は、指示された条件下で、1分間で1μmolの基質から生成物への変換を触媒する酵素の量として定義される。
PD線維芽細胞におけるrhGAAの取り込みおよびGAA活性の修正を研究するために、細胞を、10mMのNACの非存在下または存在下で、24時間、50マイクロモル/lのrhGAAとインキュベートした。未処理の細胞または比較のために使用した。インキュベーション後、細胞をトリプシン処理により回収し、凍結と融解の5サイクルによって破壊した。
GAA免疫反応性物質を研究するために、線維芽細胞抽出物をウエスタンブロット分析に供した。細胞を回収し、リン酸緩衝生理食塩水で洗浄し、水に再懸濁し、凍結融解の5サイクルによって破壊した。線維芽細胞抽出物の等量(タンパク質20μg)を、ドデシル硫酸ナトリウムポリアクリルアミドゲル電気泳動に供し、タンパク質をPVD膜(Millipore、ビルリカ、MA)に移した。GAAポリペプチドを検出するために、抗ヒトGAA抗血清を一次抗体として使用した。 βアクチンを検出するために、モノクローナルマウス抗体を使用した。免疫反応性タンパク質を、化学発光(ECL、アマシャム、フライブルク、ドイツ)によって検出した。
AlexaFluor546 で標識した GAAの分布を研究するために、カバースリップ上で増殖させたPD線維芽細胞をメタノールで固定し、0.1%サポニンを用いて透過処理し、0.01%サポニン、リン酸緩衝生理食塩水で希釈した1%ウシ胎児血清、で1時間固定した。細胞を、一次抗体で、ブロッキング溶液中で二次抗体と共にインキュベートし、次いで、ベクタシールド封入剤(Vector Laboratories社、バーリンゲーム、CA)でマウントした。試料は、ツァイスLSM 5 10レーザー走査型共焦点顕微鏡で観察した。著者らは、アルゴン/2(458、477、488、および514ナノメートル)およびHeNel(543ナノメートル)の励起レーザを使用し、2種の蛍光色素のクロストークを低減するため、別々にスイッチオンした。緑と赤の発光は、ダイクロイックスプリッタ(FT 560)によって分離され、(緑色用の515〜540 nmのバンドパスフィルターおよび赤色発光用の> 610 nmのロングパスフィルタ)で濾過した。閾値は、対照画像に見られるシグナルの〜99%を除外するために画像に適用した。
動物実験は、実験目的のために使用される動物の保護に関する欧州連合指令86/609に従って実施した。PD [ラーベンら、1993]の動物、マウスモデルは、5日間、水中の138 mMのNACを自由に(4.2g/kg/日)飲ませた。3日目には、尾静脈に単一のrhGAA注射(100mg/kg)を受けた。5日目に動物を屠殺し、組織をGAA活性について分析した。
NACは、インビトロでrhGAAの安定性を改善する
以前の研究は、温度およびpHの変更のような物理的な環境の変化は、リソソーム酵素の立体構造における摂動を誘導し、それらの安定性に影響を与えることを示した。[リーバーマンら、2007;シェンら、2008]。これらの物理的ストレスへの野生型酵素の抵抗は、一般に、薬理学的シャペロンの有効性をモニターするための指標とされる[Valenzanoら、2011]。rhGAAの安定性に対するpHの影響は、図1に示されている。
著者は異なる変異を有する5人のPD患者(PT)からの、異なる表現型(表II参照)で培養された線維芽細胞におけるNACの効果を調べた。これらの研究では、著者らは、この分子が既に臨床使用が承認されているので、したがって、NASおよびNAGと比較して臨床変換のための大きな可能性を秘めているNACに着目した。
Pt4:3つの突然変異スプライシングC-32-13T> Gとp。p.S619N(シスで);第2のアレルでp.L5552P
PER FAVORE INSERIRE INFO PER GENOTIPO PT 2 e PT 3
**活性は、線維芽細胞で測定され、解放された4-メチル-α-D-グルコピラノシド(4MU)のナノモル/ mgタンパク質/時間として表現される(対照値58.5±28.1ナノモル4MU/mgタンパク質/時間)。
著者は以前にシャペロンは、PDとファブリー病における野生型組換え酵素の有効性を高めることを示している。[ポルトら、2009;ポルトら、2011]。PD線維芽細胞におけるイミノ糖NB-DNJはrhGAAの有効性を約1.3から2倍高めた。この効果は、PDにおける、およびおそらく他のLSDにおける、ERTの有効性を改善するための可能な戦略として非常に興味深い。
rhGAAの熱変性に対するNACの効果を、イミノ糖DNJの効果と比較するために、著者らは2つのシャペロンの不在および存在下でのrhGAAの熱安定性スキャンを行った。どちらのシャペロンもDNJがTm(65.9±0.3℃)で最高のシフトを起こすと、rhGAAの熱安定性を増加させた。この結果は、明らかに、図7に示したデータとは対照的であり、NACは、PDの線維芽細胞でのrhGAAの有効性を高めるのに糖ミノよりも優れていることを示している。しかしながら、これらの結果の不一致は、細胞内での組換え酵素に対するNACの阻害効果の欠如によって説明することができる。
欠損変異酵素の救済に向けた治療戦略は、ERT、遺伝子療法および造血幹細胞の移植などの野生型酵素の供給に基づく治療に対する魅力的な代替物である。変異酵素のレスキューは、様々なアプローチにより得ることができる。一つは、タンパク質の合成、フォールディング、輸送、凝集、および分解を制御する細胞ネットワークの容量を小分子薬物で調整し、こうして小胞体からの変異タンパク質の排出を容易にする、とすることを目的とするものである。[ムーら、2008;パワーズら、2009;オングとケリー、2011; Wangら、2011]。
Claims (28)
- リソソーム酸α-グルコシダーゼ(GAA)の欠損を特徴とする病理学的状態の治療に使用するためのリソソーム酸α-グルコシダーゼ(GAA)のアロステリック非阻害性シャペロン。
- N-アセチル化アミノ酸である、請求項1に記載のアロステリック非阻害シャペロン。
- N-アセチルシステイン(NAC)、N-アセチルセリン(NAS)およびN-アセチルグリシン(NAG)からなる群より選択される、請求項1または2に記載のアロステリック非阻害シャペロン。
- 病理学的状態はリソソーム蓄積症である、請求項1〜3のいずれか一項に記載のアロステリック非阻害シャペロン。
- リソソーム蓄積症は、ポンペ病(PD)である請求項4に記載の方法。
- 少なくとも一つのリソソーム酸α-グルコシダーゼ(GAA)のアロステリック非阻害シャペロンおよび薬学的に許容される賦形剤を含む医薬組成物。
- リソソーム酸α-グルコシダーゼ(GAA)の少なくとも一つのアロステリック非阻害性シャペロン、組換えGAAおよび薬学的に許容される賦形剤を含む医薬組成物。
- さらに、「活性部位指向型」シャペロンを含む、請求項7に記載の医薬組成物。
- リソソーム酸α-グルコシダーゼ(GAA)の少なくとも一つのアロステリック非阻害性シャペロン、「活性部位特異的指向」シャペロンおよび薬学的に許容される賦形剤を含む医薬組成物。
- アロステリック非阻害シャペロンは、N-アセチル化アミノ酸である、請求項6〜9のいずれか一項に記載の医薬組成物。
- アロステリック非阻害性シャペロンは、N-アセチルシステイン(NAC)、N-アセチルセリン(NAS)およびN-アセチルグリシン(NAG)からなる群から選択される、請求項6〜10のいずれか一項に記載の医薬組成物。
- 「活性部位特異的」シャペロンは、N-ブチル-デオキシノジリマイシン(NB-DNJ)および1-デオキシノジリマイシン(DNJ)からなる群から選択される、請求項8〜11のいずれか一項に記載の医薬組成物。
- 経口または静脈内投与のためのものである、請求項6〜12のいずれか一項に記載の医薬組成物。
- リソソーム酸アルファグルコシダーゼ(GAA)のアロステリック非阻害性シャペロンの有効量を、それを必要とする患者に投与することを含む、リソソーム酸α-グルコシダーゼ(GAA)の欠損を特徴とする病理学的状態の治療方法。
- α-グルコシダーゼリソソーム酸(GAA)の欠損を特徴とする病理学的状態はリソソーム蓄積症である、請求項14に記載の方法。
- リソソーム蓄積症は、ポンペ病(PD)である、請求項15に記載の方法。
- アロステリック非阻害シャペロンは、N-アセチル化アミノ酸である、請求項14〜16のいずれか一項に記載の方法。
- アロステリック非阻害シャペロンは、N-アセチルシステイン(NAC)、N-アセチルセリン(NAS)およびN-アセチルグリシン(NAG)からなる群から選択される、請求項14〜17のいずれか一項に記載の方法。
- さらに、外因性GAAの有効量の投与および/または「活性部位指向型」シャペロンの有効量の投与を含む、請求項14〜18のいずれか一項に記載の方法。
- 「活性部位指向型」シャペロンは、N-ブチル-デオキシノジリマイシン(NB-DNJ)および1-デオキシノジリマイシン(DNJ)からなる群から選択される、請求項19に記載の方法。
- 個体における内因性および/または外因性のGAAの活性を増大させるのに有効な量のリソソーム酸α-グルコシダーゼ(GAA)のアロステリック非阻害性シャペロンを個体に投与することを含む、リソソーム酸α-グルコシダーゼ(GAA)の欠損を特徴とする病理学的状態を患っているか、または患っている疑いのある個体における内因性および/または外因性のGAAの活性を増大させるための方法。
- 内因性GAAは、野生型または変異形態であり、外因性のGAAは、組換えGAAである、請求項21に記載の方法。
- リソソーム酸α-グルコシダーゼ(GAA)の欠損を特徴とする病理学的状態は、リソソーム蓄積症、さらに好ましくは、ポンペ病である、請求項21または22に記載の方法。
- アロステリック非阻害シャペロンは、N-アセチル化アミノ酸である、請求項21〜23のいずれか一項に記載の方法。
- アロステリック非阻害性シャペロンは、N-アセチルシステイン(NAC)、N-アセチルセリン(NAS)およびN-アセチルグリシン(NAG)からなる群から選択される、請求項21〜24に記載の方法。
- アロステリック非阻害シャペロンは非リソソームのpH、好ましくは、pH7.0で野生型リソソーム酸α-グルコシダーゼ(GAA)を安定化し、および/または突然変異GAAの残存活性を増強し、および/または非リソソームpHで、好ましくはpH7.0で外因性GAAを安定化し、および/または外因性GAAの有効性を向上させる、請求項1〜25のいずれか一項に記載のアロステリック非阻害シャペロン、医薬組成物または方法。
- GAAのためのアロステリック非阻害性シャペロンを同定するためのマーカーで標識された、NACおよび/またはNASおよび/またはNAGシャペロンの使用。
- 以下の工程:
a)フルオロフォアでNACおよび/またはNASおよび/またはNAGシャペロンをラベルする工程;
b)ある量のrhGAAを該標識されたNACおよび/またはNASおよび/またはNAGに添加して基礎的なrhGAAの蛍光を得る工程;
c)基礎的なrhGAAの蛍光を測定する工程;
d)試験剤を添加する工程;
e)rhGAAの蛍光を測定する工程;
f)c)およびe)で測定したrhGAAの蛍光を比較する工程;
を含み、
ここで、蛍光の強度の変化や蛍光の波長の変化が観察された場合には、試験薬剤は、GAAのためのアロステリック非阻害性シャペロンである、
GAAためのアロステリック非阻害性シャペロンを同定するための方法。
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PCT/EP2013/061730 WO2013182652A1 (en) | 2012-06-06 | 2013-06-06 | Allosteric chaperones and uses thereof |
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Cited By (2)
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JP2019524821A (ja) * | 2016-08-11 | 2019-09-05 | イントラバイオ リミティド | リソソーム蓄積障害に関する医薬組成物及び使用 |
US11198733B2 (en) | 2016-04-27 | 2021-12-14 | Green Cross Corporation | Pharmaceutical composition for inhibiting metastasis of cancer, comprising, as active ingredient, antibody that specifically binds to epidermal growth factor receptor |
Families Citing this family (7)
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AU2015219038B2 (en) | 2014-02-18 | 2018-10-18 | Children's Hospital Los Angeles | Compositions and methods for treating neutropenia |
US10208299B2 (en) | 2014-09-30 | 2019-02-19 | Amicus Therapeutics, Inc. | Highly potent acid alpha-glucosidase with enhanced carbohydrates |
BR112018013151A2 (pt) | 2015-12-30 | 2018-12-18 | Amicus Therapeutics Inc | alfa-glicosidase ácida aumentada para o tratamento da doença de pompe |
KR102455821B1 (ko) | 2016-03-30 | 2022-10-18 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 고 m6p 재조합 단백질의 선택 방법 |
KR20240001291A (ko) | 2016-03-30 | 2024-01-03 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 재조합 산 알파-글루코시다제를 포함하는 제형 |
US20220184185A1 (en) | 2018-07-25 | 2022-06-16 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
IT202100020729A1 (it) | 2021-08-02 | 2023-02-02 | Univ Degli Studi Di Napoli Federico Ii | Preparazione combinata per il trattamento della malattia di Pompe |
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JP2005505324A (ja) * | 2001-08-31 | 2005-02-24 | クリアラント・インコーポレイテッド | 消化酵素製剤を殺菌する方法 |
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CA2736529A1 (en) * | 2008-09-23 | 2010-04-01 | Bach Pharma, Inc. | Methods of modulating protein homeostasis, metabolic syndrome, heavy metal intoxication and nrf2 transcription factors |
JP6061922B2 (ja) * | 2011-06-22 | 2017-01-18 | ザ ジェネラル ホスピタル コーポレイション | プロテイノパチーの処置方法 |
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HAWKINS, J. ET AL., MOL GENET METAB, vol. Vol.102, Issue 2, JPN6016050477, 2011, pages 20, ISSN: 0003472756 * |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11198733B2 (en) | 2016-04-27 | 2021-12-14 | Green Cross Corporation | Pharmaceutical composition for inhibiting metastasis of cancer, comprising, as active ingredient, antibody that specifically binds to epidermal growth factor receptor |
JP2019524821A (ja) * | 2016-08-11 | 2019-09-05 | イントラバイオ リミティド | リソソーム蓄積障害に関する医薬組成物及び使用 |
JP2022050564A (ja) * | 2016-08-11 | 2022-03-30 | イントラバイオ リミティド | リソソーム蓄積障害に関する医薬組成物及び使用 |
JP7393943B2 (ja) | 2016-08-11 | 2023-12-07 | イントラバイオ リミティド | リソソーム蓄積障害に関する医薬組成物及び使用 |
Also Published As
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AU2013273473A1 (en) | 2015-01-22 |
US20150147309A1 (en) | 2015-05-28 |
WO2013182652A1 (en) | 2013-12-12 |
AU2013273473B2 (en) | 2016-05-26 |
CA2915127A1 (en) | 2013-12-12 |
EP2858638A1 (en) | 2015-04-15 |
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