JP7424593B2 - エルゴチオネイン、s-メチル-エルゴチオネイン、及びそれらの使用 - Google Patents
エルゴチオネイン、s-メチル-エルゴチオネイン、及びそれらの使用 Download PDFInfo
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- JP7424593B2 JP7424593B2 JP2022505390A JP2022505390A JP7424593B2 JP 7424593 B2 JP7424593 B2 JP 7424593B2 JP 2022505390 A JP2022505390 A JP 2022505390A JP 2022505390 A JP2022505390 A JP 2022505390A JP 7424593 B2 JP7424593 B2 JP 7424593B2
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- ergothioneine
- cystine
- mice
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Description
本発明者らは、患者の尿試料中のS-メチル-L-エルゴチオネイン(S-met-L-Erg)の検出に基づくシスチン結石症の新規な診断方法を開発した。
(b1)S-メチル-L-エルゴチオネインの量が腎疾患に罹患している対象の基準値の範囲内にある場合、治療的介入を開始することを決定又は推奨する工程;又は代わりに、
(b2)対象の単離された試料中のS-メチル-L-エルゴチオネインの前記量を基準値(腎疾患に罹患していない対象の前記基準値)と比較する工程であって、工程(a)で測定されたS-メチル-L-エルゴチオネインの量が基準値よりも少ない場合、対象が治療的介入を開始しなければならないことを示している工程
を含む方法を提供する。
驚くべきことに、以下の例に示されるとおり、本発明者らは、エルゴチオネイン(Erg)の投与が、シスチン尿症マウスモデルにおける腎結石の出現を防止又は遅延させることを見い出した。
本出願において、本明細書に使用されるとき全ての用語は、特に断りない限り、当技術分野で既知のその通常の意味で理解されるものとする。本出願において使用されるとき特定の用語の他のより具体的な定義は、以下に明記され、そして他に明示的に定められた定義がより広い定義を提供しない限り、明細書及び特許請求の範囲の至るところで一様に適用されることが意図される。
エルゴチオネインは、[1-カルボキシ-2-(2-スルファニリデン-1,3-ジヒドロイミダゾール-4-イル)エチル]-トリメチルアザニウムというlUPAC名、CAS番号497-30-3、及び式(I):
更には、本発明のキットは、S-メチル-L-エルゴチオネイン及び/又はL-エルゴチオネインの量を決定するためのキットに含まれる様々な手段の同時、連続又は別々の使用のための取扱説明書を含有することができる。前記取扱説明書は、印刷物の形態、或いは、例えば、電子記憶媒体(例えば、磁気ディスク、テープ)、又は光学媒体(例えば、CD-ROM、DVD)、又はオーディオ素材などの、読み取られやすいか又は理解されやすい取扱説明書を記憶することができる電子的支援の形態であり得る。追加的に、又は代わりに、媒体は、前記取扱説明書を提供するインターネットアドレスを含有することができる。
(a)対象の単離された試料、特に尿試料において、酸化還元電位(ORP)を測定すること;
(b)(a)のORPを基準値と比較すること;及び
(c)(c1)ORPが結石非形成対象の基準値の範囲内にある場合、或いは(c2)ORPが基準値よりも低い場合、対象を結石非形成対象と診断すること(前記基準は、以前に結石形成対象として分類された対象から得られた)
を含む。
(a)対象の単離された試料中のS-メチル-L-エルゴチオネインの量、及び任意選択でL-エルゴチオネインの量を測定し、S-メチル-L-エルゴチオネインとL-エルゴチオネインの量の比を算出する工程;
(b)(a)で測定された量又は比を基準値と比較する工程;及び
(c1)(a)で測定されたレベルが、腎結石症又はアミノ酸尿症に罹患していない対象の基準値よりも低い場合、或いは(c2)(a)で測定されたレベルが、腎結石症又はアミノ酸尿症に罹患している対象の基準値の範囲内にある場合、薬学的に有効量のシスチン可溶化剤をそれを必要としている対象に投与する工程
を含む方法を提供する。
(a)対象の単離された試料中のS-メチル-L-エルゴチオネインの量、及び任意選択でL-エルゴチオネインの量を測定し、S-メチル-L-エルゴチオネインとL-エルゴチオネインの量の比を算出する工程;
(b)(a)で測定された量又は比を基準値と比較する工程;及び
(c1)(a)で測定されたレベルが、腎結石症又はアミノ酸尿症に罹患していない対象の基準値よりも低い場合、或いは(c2)(a)で測定されたレベルが、腎結石症又はアミノ酸尿症に罹患している対象の基準値の範囲内にある場合、薬学的に有効量のエルゴチオネインをそれを必要としている対象に投与する工程
を含む方法を提供する。
更に、「含む」という単語は、「からなる」の場合を包含する。本発明の追加の目的、利点及び特徴は、説明を検討することで当業者に明らかになるか、又は本発明の実施によって学ぶことができる。以下の実施例及び図面は、例示として提供されており、本発明を限定することを意図するものではない。図面に関連し、請求の範囲の括弧内に配置された参照記号は、請求の範囲の明瞭性を高めることのみを目的としており、請求の範囲を制限するものと解釈されるべきではない。更には、本発明は、本明細書に記載の特定の好ましい実施態様の全ての可能な組合せに及ぶ。
実施例
マウスの飼育
全ての動物プロトコールは、IDIBELL(AAALAC認証施設、B9900010)の動物実験倫理委員会、及びEU指令2010/63/EUによる対応するカタルーニャ州政府(Department of Generalitat de Catalunya)によって承認された。実験は、最高の科学的、人道的、及び倫理的原則に基づいて実施された。全ての動物は純粋な遺伝的背景C57BL/6Jであり、湿度と温度が制御された部屋で12時間の明暗サイクルで維持された。動物は、食餌(Teklad Global 14% Protein Diet、Harlan Laboratories)と水を自由に摂取できる無菌ケージに収容された。
Slc7a9-/-(シスチン尿症のマウスモデル)及びSlc22a4-/-(Feliubadalo et al“Slc7a9-deficient mice develop cystinuria non-l and cystine urolithiasis” Hum Mol Genet 2003; vol 12; pp. 2097-2108; Kato Y. et al.,“Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1”, Pharm. Res., 2010; vol 27, pp. 832-40)の単一機能喪失マウスモデルを交配して、二重ヘテロ接合体マウスを入手し、これらを戻し交配して、二重KO Slc7a9-/- Slc22a4-/-(dKO)を含む、3種の予想される遺伝子型を取得した。
各遺伝子型のマウスを個別に代謝ケージに4日間収容し、最初の日を適応期間とした。マウスの体重、水分及び食餌の摂取量、並びに排泄された糞便及び尿が毎日モニターされた。24時間尿試料を収集し、保存料としてイソプロパノール中の10%チモール50pLを用いて更に分析するまで-80℃で保存した。EDTAでコーティングされた注射器を用いた心臓内穿刺によって採血して、Microvette EDTA-チューブ(Sarstedt)に血液を移し、室温で10分間インキュベートした後、ミニフュージで3000rpmで10分間及び4℃で遠心分離した。次に血漿を新しいチューブに分離し、氷上に置いた。次に、414nmでの血漿吸光度を測定することによって、NanoDrop分光光度計で溶血を定量して、OD<0.2の溶血のみに更なる分析が考慮された。血漿試料は-80℃で保存され、そして遠心分離された赤血球(RBC)も収集されて-80℃で保存された。
血漿及び赤血球中のL-Ergは、Sotgia S. et al. “Plasma L-ergothioneine measurement by high-performance liquid chromatography and capillary electrophoresis after a pre-column derivatization with 5-iodoacetamidofluorescein (5-IAF) and fluorescence detection”. Antopolsky M, ed. PLoS One 2013; vol. 8: e70374により記載されるとおり、一方、血漿クレアチニンは(Zinellu A. et al.,“Assay for the simultaneous determination of guanidinoacetic acid, creatinine and creatine in plasma and urine by capillary electrophoresis UV-detection”, J. Sep. Sci., 2006)により記載されるとおり測定された。
解凍した尿試料中のクレアチニン濃度は、10kDa MWCOスピンフィルター(Amicon Ultra 0.5mL、Millipore)で濾過した後に、製造業者の指示どおりにクレアチニンアッセイキット(Sigma)で測定した。
血中及び尿中のL-Erg濃度の性差及び月齢差
本発明者らは、最初に、wt及びSlc7a9-/-オスのマウスの血中及び尿中のL-Erg含量を分析して、差次的発現によって説明できる差を探した。血液、血漿又は赤血球(RBC)中のL-Erg濃度は、wt及びシスチン尿症のオスのマウスの間に有意な差を示さず、血漿及び血液中の濃度はSlc7a9-/-オスのマウスで高く、RBC中では低くなっていた(データは示されていない)。RBC中のL-Erg濃度は血漿中よりも2桁高かったため、血漿中のL-Ergの測定における溶血の推定効果を説明するために、L-Ergの血漿濃度に対する溶血の寄与を分析し、両方の変数間に相関関係がない(データは示されていない)ことを見い出した。L-Ergの尿中濃度もSlc7a9-/-オスのマウスで有意でない増加を示したが(図1)、予期しないことに、S-met-L-Erg(L-Ergの代謝物)の濃度はSlc7a9-/-オスのマウスで有意な低下を示した(図1)。これらの結果は、尿中のS-met-L-Ergがシスチン結石症のバイオマーカーとして使用できることを示している。
シスチン尿症の特徴の1つは、シスチン尿症の患者及びマウスにシスチン結石が存在することである。したがって、本発明者らは、3か月齢及び6か月齢の結石形成及び結石非形成のシスチン尿症マウスにおけるL-Erg及びS-Met-L-Ergの尿中濃度を分析した(図4)。L-Ergの尿中濃度は、早期結石形成(ESF)メスのマウスで有意に低かった(図4A)が、一方S-Met-L-Ergは3か月齢のESFメス(図4A)及び両方の月齢のESFオスで高かった(図4A~B、3か月齢オスでP=0.062)。両性の間の差は、両方の月齢のL-ErgとS-Met-L-Ergの両方で確認でき、3か月齢のL-Erg濃度を除いて、一般にメスで濃度が低くなっている(図4A~B)。本発明者らは、S-Met-L-Ergの尿中濃度を使用して、受信者動作特性(ROC)曲線を用いてマウスの結石症表現型を識別できるかどうかを調査し、0.65を上回る曲線下面積を得たが、これは、S-met-L-Ergが結石症のバイオマーカーとして使用できることを示している。
マウスの飼育は実施例1に示されているとおりとした。
L-Erg処置
3つの異なる処置がマウスに適用された:1か月、3か月~結石症マウス(中期)及び6か月(長期曝露)。全ての場合において、L-Ergは飲料水中で投与された。
イソフルラン麻酔マウスは、対応する図の凡例に既知の重量のシスチン結石の検量線で示される月齢で、IVIS Lumina XR Series III (Caliper Lifescience - Vertex Techniques)で製造業者のイメージングパラメーターにより、結石症の検出及び経過観察のためにX線イメージングに付した。結石の定量は、機器に付属のLiving Image Softwareを使用して、結石の面積を手動で範囲を定めることによって行われ、そして推定重量は検量線から補間された。
任意の処置期間の最終週に、マウスを個別に代謝ケージに4日間収容し、最初の日を適応期間とした。マウスの体重、水分及び食餌の摂取量、並びに排泄された尿が毎日モニターされた。24時間尿試料を収集し、保存料としてイソプロパノール中の10%チモール50pLを用いて更に分析するまで-80℃で保存した。pHは、pHメーター(カタログ番号5209、Crison)を使用して測定され、酸化還元電位は、室温でmicropH 2000(Crison)でORP電極(カタログ番号5265、Crison)を使用して測定された。
解凍した尿試料中のクレアチニン濃度は、10kDa MWCOスピンフィルター(Amicon Ultra 0.5mL、Millipore)で濾過後、製造業者の指示どおりにクレアチニンアッセイキット(Sigma)で測定された。
L-Ergのそれ自体との及びCysとの反応性を、0.2M Na2HP04中pH=7.2及びホウ酸緩衝液(ref. 33650-1L、Fluka)中pH=11の2つの条件でRTで17時間インビトロでアッセイした。L-Erg-L-Erg及びL-Erg-Cys二量体、並びにシスチンの存在は、LC/MS-MSによって測定された。
ノンパラメトリック分析(ウィルコクソン・マン・ホイットニー検定)を使用して、Rstudioを用いて有意性を評価した。p<0.05の場合、統計的有意性は肯定的と見なされる。
最初に、飲料水中の2種の異なる濃度(15及び60mg/L)での1か月のL-Erg処置が、水分摂取量、並びに尿pH及びORP、及びL-Erg濃度に及ぼす効果を調査することにより、マウスを処置するための最適な実用的用量を特定した。以下の観察が行われた:
i)特にメス(性別データは示されていない)において、表面積によって正規化された水分摂取量(図6A)の試験されたL-Erg濃度での処置の終了時に統計的に有意でない増加(それぞれp=0.11及びp=0.08);ii)特にオス(データは示されていない)において、60mg/LでのpH(図6B)の統計的に有意な増加、及び15mg/LでのpHの統計的に有意でない増加(p=0.052);iii)尿の酸化還元状態又は酸化還元電位(ORP)(図6C)の統計的に有意でない減少;並びにiv)尿中のL-Erg及びS-Met-L-Erg濃度の統計的に有意な増加(それぞれ図6D及び6E)。興味深いことに、L-Erg及びS-Met-L-Ergの尿中濃度の差は、両方の試験条件間で見い出された。15mg/Lでは、L-Erg及びS-Met-L-Ergの濃度は、それぞれ3倍(3.4±0.4)及び6倍(5.9±0.6)増加した。60mg/Lでは、L-Erg及びS-Met-L-Ergの増加は、それぞれ175倍(174.6±38.4)及び15倍(14.7±1.9)であった。これらの差は、60mg/Lでは、L-Ergの内部貯留及び代謝が飽和に近い可能性があることを示唆している。尿中の利用可能なL-Ergの量を最大化するために、13.6±1.6mg/kg・日の平均±SEM算出用量に対応する、飲料水中のL-Erg 60mg/Lの濃度を、更なるアッセイのために採用した(データは示されていない)。
最初に、処置マウス及び未処置マウスの両方で3か月間、X線でシスチン結石の成長を毎月モニターすることにより、結石症マウスのシスチン結石の進行に及ぼすL-Erg処置(飲料水に60mg/L)の効果を確認した。試験条件でのシスチン結石の成長に及ぼす処置の効果(p=0.61)は観察されなかった(図7)。シスチン尿症のマウスは複数又は単一の結石を持つ可能性があるため、それぞれのタイプに効果があるかどうかも分析された。単一又は複数の結石のいずれについても統計的に有意な効果は観察されなかった(それぞれp=0.78及びp=0.41;データは示されていない)。様々な代謝パラメーターに及ぼす処置の効果を調べるために、尿のpH及び酸化還元状態、並びに表面積で補正された水分摂取量に及ぼす効果も分析して、処置前後のL-Erg処置動物で差は観察されなかった(データは示されていない)。実験中の推定平均±SEM L-Erg用量は(17.24±0.69mg/kg・日)であった。
次に、離乳から6か月間シスチン尿症マウスを処置することにより、L-Ergがシスチン結石形成に何らかの効果を及ぼすかどうかを試験した。成体マウスでの以前の実験を考慮して、16mg/kg・日の標的用量を設定した。成長中のマウスでそれを達成するために、実験全体を通してマウスの成長及び水分摂取量をモニターし、Tordoffらの結果に基づいて体表面積によって補正された水分摂取量を考慮して飲料水中のL-Erg濃度を調整した(Tordoff MG, Bachmanov AA, Reed DR. Forty mouse strain survey of water and sodium intake. Physiol. Behav. 2007; 91 : 620-31を参照のこと)。6か月間の推定平均±SD用量は16.25±6.29であった(データは示されていない)。結石症の発症に及ぼす効果を分析するために、処置マウス及び未処置マウスを、6か月の処置期間中、毎月X線イメージングにより経過観察した。結石症マウスの数の50%の減少、マウスの性別とは無関係に結石症の発症の遅延(図8A)(データは示されていない)、及びL-Erg処置群における結石成長のほぼ統計的に有意な減少(図8B)が観察された。
L-Ergの抗酸化能力は、尿の酸化還元電位の低下を説明するかもしれないが、それ自体では、結石症の減少と、実行された2つの異なる処置間の結石成長速度で観察された差を説明しない。シスチン結石症に対するL-Ergの作用機序に関する洞察を得るために、LC/MS-MSにより2つの条件pH=7.2及びpH=11でのインビトロでの二量体L-Erg-Cysの形成を最初に分析した(データは示されていない)。L-Erg-CysもL-Erg-L-Erg二量体も検出されなかったが、これは、L-Ergの作用機序が、L-Cysの一部を抑制することによるL-Cys濃度の低下を意味するものではないことを示唆している。
選択されたドラッグデリバリーシステムは、用量を制御するのにあまり適切ではないと見なすことができる。それが大きな変動を促すのは事実であるが、L-Ergの血中及び血漿中濃度は6週間有意に高いままであり、投与後1週間の尿中濃度は5mg/kg・日相当に終わるため、マウスが摂取したL-Ergの用量の低下が、処置動物で観察された結石症の原因である可能性があると主張するのは難しい。
発明者らは、シスチン結石を形成しないシスチン尿症マウスの尿ORPが、結石を形成するマウスの尿ORPよりも低いことに気付いた。よって、このパラメーター(実施例2に示されるように測定される)はまた、ヒトを含むシスチン尿症の動物におけるインビトロの鑑別的予後判定についても提案される。
マウスの飼育は実施例1と同じとした。
マウスを個別に代謝ケージに4日間収容し、最初の日を適応期間とした。マウスの体重、水分及び食餌の摂取量、並びに排泄された尿が毎日モニターされた。24時間尿試料を収集し、保存料として10mM アジ化ナトリウムを使用して更に分析するまで-80℃で保存した。酸化還元電位は、室温でmicropH 2000(Crison)でORP電極(Crison)を使用して新鮮尿で測定された。
ORPは結石形成マウスでより高い
尿ORPは、C57BL6/Jの遺伝的背景におけるシスチン尿症の2つの異なるマウスモデル(Slc7a9-/-(Feliubadalo et al.、上記)又はSlc3a1D140G)のシスチン尿症マウスで有意に高かった。Slc3a1D140Gモデルは、Peter et al.,“A mouse model for cystinuria type I”, Hum Mol Genet.- 2003 vol. 1 ; 12(17), pp. : 2109-20により開示されている。I型シスチン尿症マウスモデル 129S2/SvPasCrl(Slc3a1E383K)からの予備データは、アッセイ時にモデルによって生成される散発性のシスチン結石の量が非常に限られている割には、同様の結果を示した。これらのデータは全て図10に示され、尿ORPがシスチン結石症の診断又は予後判定に役立つ可能性があることを明確に示している。両方の性別を考慮すると、傾向は全ての群で保持されているが、C57BL6/JにおけるSlc7a9-/-のオス及びSlc3a1D140Gのメスのみが尿ORPの有意な減少を示した(性別データは示されていない)。
Claims (5)
- 腎結石症又はアミノ酸尿症の処置及び/又は予防に使用するための、エルゴチオネインを含む医薬組成物であって、アミノ酸尿症がシスチン尿症である、医薬組成物。
- 腎結石症又はアミノ酸尿症の処置及び/又は予防における、追加のシスチン可溶化剤、L-シスチンジメチルエステル、L-シスチンメチルエステル、L-シスチンジアミド、リポ酸、及びそれらの組合せからなる群より選択される化合物との併用療法に使用するための、エルゴチオネインを含む医薬組成物であって、アミノ酸尿症がシスチン尿症である、医薬組成物。
- 1つ以上の薬学的に許容し得る賦形剤及び/又は担体を含む、請求項1又は2記載の医薬組成物。
- エルゴチオネインがL-エルゴチオネインである、請求項1~3のいずれか一項記載の医薬組成物。
- 1日あたり0.01~500mg/kg体重の用量でエルゴチオネインを投与するための、請求項1~4のいずれか一項記載の医薬組成物。
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北川 照男, I.尿検査 17.アミノ酸尿, 臨時増刊特集 これだけは知っておきたい検査のポイント 第3集,[令和5年8月 15日検索],[online], 1984, p.2114,インターネット<URL: https://webview.isho.jp/journal/detail/abs/10.11477/mf.1402219338?p=firstTab> |
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