JP7395161B2 - 老化細胞除去薬 - Google Patents
老化細胞除去薬 Download PDFInfo
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- JP7395161B2 JP7395161B2 JP2022043458A JP2022043458A JP7395161B2 JP 7395161 B2 JP7395161 B2 JP 7395161B2 JP 2022043458 A JP2022043458 A JP 2022043458A JP 2022043458 A JP2022043458 A JP 2022043458A JP 7395161 B2 JP7395161 B2 JP 7395161B2
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
[1] SGLT2阻害薬を含有する、老化細胞除去薬。
[2] SGLT2阻害薬が、低分子化合物、SGLT2発現阻害薬及びSGLT2特異的結合物質からなる群より選ばれる少なくとも1つである、上記[1]記載の老化細胞除去薬。
[3] SGLT2阻害薬が、カナグリフロジン、エンパグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン、及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも1つである、上記[1]又は[2]記載の老化細胞除去薬。
[4] SGLT2阻害薬及び薬学的に許容される担体を含有する、老化細胞除去用医薬組成物。
[5] 老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するための、上記[4]記載の医薬組成物。
[6] 老化細胞を除去することにより病態の改善が見込まれる疾患が老化関連疾患である、上記[5]記載の医薬組成物。
[7] SGLT2阻害薬及び薬学的に許容される担体を含有する、老化関連疾患の予防又は治療のために使用される医薬組成物。
[8] 老化関連疾患が、心不全、動脈硬化症、動脈硬化性の脳心血管疾患、高血圧症、脳梗塞、脳出血、脂質異常症、肺線維症、肺気腫、骨格筋萎縮(サルコペニア)、変形性関節症、認知症、フレイル、がん、慢性腎臓病、白内障、緑内障、加齢黄斑変性症、老眼、加齢性脱毛、加齢性難聴、加齢に伴う腰痛・関節痛などの痛み、皮脂欠乏性湿疹、皮膚掻痒症、脂肪肝、非アルコール性脂肪肝炎(NASH)、肝硬変、骨粗鬆症、変形性骨関節症、ハッチンソン・ギルフォード・プロジェリア症候群、ウエルナー症候群、コケイン症候群、及びロスモンド・トムソン症候群からなる群より選ばれる少なくとも1つである、上記[6]又は[7]記載の医薬組成物。
[9] SGLT2阻害薬が、カナグリフロジン、エンパグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン、及びこれらの薬学的に許容される塩から選択される少なくとも1つである、上記[4]~[8]のいずれかに記載の医薬組成物。
[10] 老化細胞除去用医薬を製造することにおける、SGLT2阻害薬の使用。
[11] 老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するための医薬を製造することにおける、SGLT2阻害薬の使用。
[12] 老化細胞を除去するための方法であって、有効量のSGLT2阻害薬を、それを必要とする対象に投与することを含む、方法。
[13] 老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するための方法であって、有効量のSGLT2阻害薬を、それを必要とする対象に投与することを含む、方法。
別の実施態様において、本発明は、老化細胞除去用医薬或いは老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するための医薬を製造することにおける、SGLT2阻害薬の使用を提供する。
更に別の実施態様において、本発明は、老化細胞を除去するための方法或いは老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するための方法であって、有効量のSGLT2阻害薬を、それを必要とする対象に投与することを含む、方法を提供する。
なお更に別の実施態様において、本発明は、老化細胞を除去するために使用される又は老化細胞を除去することにより病態の改善が見込まれる疾患を予防又は治療するために使用されるSGLT2阻害薬を提供する。
特に好ましい実施態様においては、上記の老化細胞除去薬、医薬組成物、医薬などにおいて、SGLT2阻害薬を有効成分として含有する。
本明細書における「老化細胞」とは、正常な細胞に比べて老化マーカーの発現量の上昇を示す細胞を意味する。老化マーカーとしては、老化関連酸性β-ガラクトシダーゼ、P53、P16INK4a、P21CIP1などが挙げられる。老化細胞は、G1期の不可逆的な増殖停止によって特徴付けられ、細胞周期の進行を促す遺伝子の抑制と、細胞周期を阻害するp53、p16INK4a、p21CIP1の発現上昇が関与して形成されることが知られている。
老化細胞は、分裂が停止しているが代謝的には活性なままの細胞であり得る。非分裂細胞は、何週間も生存可能であり得るが、培地中の十分な空間、栄養素、増殖因子の存在にもかかわらず、DNAを増殖・複製することができない。したがって、老化細胞に生理的刺激を加えても、老化細胞を刺激して増殖させることはできないので、この分裂の停止は、本質的に永久的なものとなる。
老化細胞は、非老化細胞とは、以下の1つ又はそれ以上の点において、異なり得る:1)老化細胞は増殖を停止し、生理的なマイトジェンによる細胞周期に再び入るように刺激することができない;2)老化細胞は、アポトーシス性の細胞死に耐性になる;3)老化細胞は、変化した分化機能を獲得する。
本明細書における「老化細胞除去」とは、老化細胞を組織又は器官などから取り除くことを意味するか、又は老化細胞を死滅させることを意味する。同じ濃度で老化細胞ではない細胞(以下、「非老化細胞」という。)が有意には死滅されず、老化細胞が選択的又は特異的に死滅されることが特に好ましい。
したがって、好ましくは、本発明で使用されるSGLT2阻害薬の非老化細胞における50%致死濃度(Lethal Concentration 50、以下、「LC50」という。)は、当該SGLT2阻害薬の老化細胞におけるLC50よりも、約2~約50倍高くあり得る。LC50とは、細胞サンプル中の細胞の半分を死滅させるのに必要な濃度である。例えば、非老化細胞におけるLC50は、老化細胞におけるLC50よりも、約2倍以上、約3倍以上、約4倍以上、約5倍以上、約6倍以上、約7倍以上、約8倍以上、約9倍以上、約10倍以上、又はそれ以上高くてもよい。或いは、非老化細胞におけるLC50は、老化細胞におけるLC50よりも、約10倍以上、約15倍以上、約20倍以上、約25倍以上、約30倍以上、約35倍以上、約40倍以上、約45倍以上、約50倍以上、又はそれ以上高くてもよい。
本明細書における「老化関連疾患」には、対象における細胞若しくは細胞集団における非増殖性又は老化性の状態が誘導されるか或いは維持されることによって全体的又は部分的に媒介される任意の疾患或いは状態が含まれ得る。老化関連疾患には、病状の兆候を目視することができないような組織又は器官の衰退、或いは、変性疾患や機能低下障害などの目視可能な病状が含まれ得る。
(SGLT2阻害薬)
SGLT2阻害薬である低分子化合物としては、例えば、カナグリフロジン[(1S)-1,5-Anhydro-1-C(-3{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-D-glucitol]、エンパグリフロジン[(1S)-1,5-Anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol]、イプラグリフロジン[(1S)-1,5-Anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D-glucitol]、ダパグリフロジン[(1S)-1,5-Anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol]、ルセオグリフロジン[(2S,3R,4R,5S,6R)-2-{5-[(4-Ethoxyphenyl)methyl]-2-methoxy-4-methylphenyl}-6-(hydroxymethyl)thiane-3,4,5-triol]、トホグリフロジン[(1S,3’R,4’S,5’S,6’R)-6-[(4-Ethylphenyl)methyl]-6’-(hydroxymethyl)-3’,4’,5’,6’-tetrahydro-3H-spiro[2-benzofuran-1,2’-pyran]-3’,4’,5’-triol]、セルグリフロジンエタボナート[2-(4-Methoxybenzyl)phenyl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside]、レモグリフロジンエタボナート[5-Methyl-1-(propan-2-yl)-4-[[4-[(propan-2-yl)oxy]phenyl]methyl]-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside]、エルツグリフロジン[(1S,2S,3S,4R,5S)-5-[4-Chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol]、ソタグリフロジン[Methyl (5S)-5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-β-L-xylopyranoside]、及びこれらの薬学的に許容される塩が挙げられる。これらの化合物は、公知の製造方法又は当該方法に改変を施した任意の製造方法により、製造することができる。
SGLT2発現阻害薬としては、例えば、siRNA、shRNA、miRNA、リボザイム、アンチセンス核酸、低分子化合物などが挙げられる。これらの発現阻害薬を投与することにより、SGLT2の発現を阻害することができる。
細胞内に導入されたsiRNAは、RNA誘導サイレンシング複合体(RISC)と結合する。この複合体はsiRNAと相補的な配列を持つmRNAに結合し切断する。これにより、配列特異的に遺伝子の発現を抑制する。
SGLT2特異的結合物質としては、SGLT2に特異的に結合してSGLT2の機能を阻害するものが挙げられ、例えば、抗体、抗体断片、アプタマーなどが挙げられる。抗体は、例えば、マウス等の動物に、SGLT2タンパク質又はその断片を抗原として免疫することによって作製することができる。或いは、抗体は、例えば、ファージライブラリーのスクリーニングにより作製することができる。抗体断片としては、Fv、Fab、scFvなどが挙げられる。抗体は、モノクローナル抗体であることが好ましい。また、抗体は、市販の抗体であってもよい。アプタマーは、標的物質に対する特異的結合能を有する物質である。アプタマーとしては、核酸アプタマー、ペプチドアプタマーなどが挙げられる。標的ペプチドに特異的結合能を有する核酸アプタマーは、例えば、systematic evolution of ligand by exponential enrichment(SFLEX)法などにより選別することができる。また、標的ペプチドに特異的結合能を有するペプチドアプタマーは、例えば酵母を用いたTwo-hybrid法などにより選別することができる。
(肥満モデルマウスの作製)
4週齢の野生型マウス(C57BL/6NCr)に8週間高脂肪食を与え、摂餌性肥満モデルマウスを作製した。続いて、作製した肥満モデルマウスにSGLT2阻害薬であるカナグリフロジンを0.03%W/W混餌経口投与した(以下、「高脂肪食+SGLT2i群」という。)。
(老化関連酸性β-ガラクトシダーゼ活性の検討)
実験例1において、カナグリフロジンの投与開始から1週間後に各群のマウスから内臓脂肪組織(精巣周囲脂肪組織)を採取した。
(p53タンパク質の発現量の検討)
p53タンパク質は、細胞老化を促進する老化促進分子として中心的役割を担うことが知られている。本発明者は、以前に、肥満ストレスを加えると、内臓脂肪組織においてp53シグナルの上昇を介した細胞老化反応が促進され、内臓脂肪炎症が惹起され、全身の代謝不全が生じ、糖尿病の病態が形成、増悪することを明らかにした。そこで、肥満モデルマウスの脂肪組織におけるp53タンパク質の発現を検討した。
その結果、肥満モデルマウスにSGLT2阻害薬を投与することにより、内臓脂肪組織におけるp53の発現量が頑著に低下することが明らかとなった。この結果は、SGLT2阻害薬の投与により、老化細胞が除去されることを更に支持するものである。
(老化マーカーp21(Cdkn1a)及びp16(Cdkn2a)のmRNA発現量の検討)
P53と共に老化シグナルとして重要な働きを担っているp21及びp16のmRNA発現について検討した。
(脂肪炎症及び脂肪組織の酸化ストレスへの影響の検討)
肥満の内臓脂肪組織ではマクロファージを主体とした炎症細胞浸潤が生じ、crown-like structure(CLS)と呼ばれる細胞死に陥った脂肪細胞をマクロファージが取り囲み貪食・処理する特徴的な組織構造がみられると共に、酸化ストレスが亢進する。そこで、SGLT2阻害薬の肥満モデルマウスの白色脂肪組織における脂肪老化、脂肪炎症への影響について検討した。
図5(a)は、DHE染色によって酸化ストレスを評価した結果を示す写真である。スケールバーは100μmを示す。図5(b)は、DHE陽性エリアの測定結果のグラフである。高脂肪食によって亢進した酸化ストレスも、SGLT2阻害薬の投与で顕著に抑制された。
図6(a)は、quantitive RT-PCRの結果を示したグラフである。図6(b)はF4/80の免疫蛍光染色を示した写真である。SGLT2阻害薬の投与により、脂肪組織中へのマクロファージの浸潤は残るものの、CCL2及びTNFαといった炎症関連分子のmRNA発現の低下傾向が見られた。以上の結果から、SGLT2阻害薬は肥満モデルにおいて、脂肪老化の改善に伴って脂肪炎症や酸化ストレスをも軽減させることが明らかとなった。
(内臓脂肪組織以外の臓器における老化シグナルに及ぼす影響の検討)
SGLT2阻害薬が内臓脂肪組織以外の臓器の老化シグナルに対しても抑制効果を示すか否かについても検討した。
(動脈硬化モデルマウスでの検討)
SGLT2阻害薬が動脈硬化モデルマウスの血管の老化細胞を除去する効果を示すか否かについて検討した。
(早老症モデルマウスでの検討)
13週齢のハッチンソン・ギルフォード早老症モデルマウス(Zmpste24欠失マウス)にSGLT2阻害薬カナグリフロジンを0.03%W/W混餌経口投与し、マウスの一般状態を観察した。
(培養老化細胞での検討)
短期間のSGLT2阻害薬の投与で老化細胞が減少したマウスの血液及び各種組織のメタボローム解析を実施した結果、血中ならびに各組織におけるケトン体濃度の増加や血中AICAR(5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside)の有意な増加を認めた。また、SGLT2阻害により脂肪酸酸化が亢進し解糖系の抑制がみられること、及び老化細胞では解糖系の亢進がみられることが知られている。そこで、3-Hydroxybutyrate(以下、「3HB」という。)、AICAR(以下、「AIC」という。)及び解糖系抑制効果を持つ2-deoxyglucose(以下、「2DG」という。)が老化細胞の細胞死誘導作用を有するかについて検討した。
また、本発明の精神から逸脱することなく、本明細書に記載した実施態様に任意の改変を加えることができることは当業者には明らかであり、そのような改変物も、本発明の範囲に包含される。
Claims (4)
- 骨格筋萎縮(サルコペニア)、認知症、フレイル、ハッチンソン・ギルフォード・プロジェリア症候群、ウエルナー症候群、コケイン症候群、及びロスモンド・トムソン症候群からなる群より選ばれる少なくとも1つの疾患を予防又は治療するための、SGLT2阻害薬を含有する医薬組成物であって、
SGLT2阻害薬が、カナグリフロジン、エンパグリフロジン、イプラグリフロジン、ダパグリフロジン、ルセオグリフロジン、トホグリフロジン、セルグリフロジンエタボナート、レモグリフロジンエタボナート、エルツグリフロジン、ソタグリフロジン、及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも1つである、医薬組成物。 - SGLT2阻害薬が、カナグリフロジン、エンパグリフロジン、及びこれらの薬学的に許容される塩からなる群より選ばれる少なくとも1つである、請求項1に記載の医薬組成物。
- 疾患が、ハッチンソン・ギルフォード・プロジェリア症候群、ウエルナー症候群、コケイン症候群、及びロスモンド・トムソン症候群からなる群より選ばれる少なくとも1つであり、
SGLT2阻害薬が、カナグリフロジン又はその薬学的に許容される塩である、請求項1又は2に記載の医薬組成物。 - 疾患が、ハッチンソン・ギルフォード・プロジェリア症候群であり、
SGLT2阻害薬が、カナグリフロジン又はその薬学的に許容される塩である、請求項3に記載の医薬組成物。
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