JP6429401B2 - 変異を有するi型コラーゲンの小胞体内過剰蓄積正常化剤 - Google Patents
変異を有するi型コラーゲンの小胞体内過剰蓄積正常化剤 Download PDFInfo
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- JP6429401B2 JP6429401B2 JP2016173863A JP2016173863A JP6429401B2 JP 6429401 B2 JP6429401 B2 JP 6429401B2 JP 2016173863 A JP2016173863 A JP 2016173863A JP 2016173863 A JP2016173863 A JP 2016173863A JP 6429401 B2 JP6429401 B2 JP 6429401B2
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Description
[1]変異を有するI型コラーゲンの小胞体内過剰蓄積正常化剤であって、4−フェニル酪酸またはその薬学的に許容される塩を有効成分とすることを特徴とする剤。
[2]4−フェニル酪酸の薬学的に許容される塩が4−フェニル酪酸ナトリウムである前記[1]に記載の剤。
[3]前記[1]または[2]に記載の剤を含有する、I型コラーゲンの変異に起因する疾患の治療用医薬。
[4]I型コラーゲンの変異に起因する疾患が、骨形成不全症、カフィー病またはエーラス・ダンロス症候群である前記[3]に記載の医薬。
[5]小胞体内I型コラーゲン過剰蓄積を伴う疾患が、骨形成不全症である前記[3]に記載の医薬。
変異を有するI型コラーゲンの小胞体内過剰蓄積を正常化する方法であって、哺乳動物に対して4−フェニル酪酸またはその薬学的に許容される塩を投与することを特徴とする方法。
変異を有するI型コラーゲンの小胞体内過剰蓄積正常化に使用するための4−フェニル酪酸またはその薬学的に許容される塩。
変異を有するI型コラーゲンの小胞体内過剰蓄積正常化剤を製造するための4−フェニル酪酸またはその薬学的に許容される塩の使用。
哺乳動物に対して4−フェニル酪酸またはその薬学的に許容される塩を投与することを特徴とするI型コラーゲンの変異に起因する疾患の治療方法。
I型コラーゲンの変異に起因する疾患の治療に使用するための4−フェニル酪酸またはその薬学的に許容される塩。
I型コラーゲンの変異に起因する疾患の治療用医薬を製造するための4−フェニル酪酸またはその薬学的に許容される塩の使用。
1.材料と方法
(1)細胞
骨形成不全症患者(COL1A1遺伝子にc.2461G>A (p.G821S)の変異を有する)から手術の際に採取した皮膚線維芽細胞を使用した。正常細胞として、初代ヒト皮膚線維芽細胞新生児(Human Dermal Fibroblasts, neonatal, Gibco, Cat.# C0045C)を用いた。継代数5〜6の細胞を用いて実験を行った。これらの細胞を96ウェルプレートに6〜8×103個/ウェルで播種し、通常の皮膚線維芽細胞の培養液であるDMEM(Wako)、10%FBS(Equitech Bio)、0.5%ペニシリン−ストレプトマイシン(Gibco)に、ケミカルシャペロンを添加するウェル、添加しないウェルを設けて2日間培養した。
ケミカルシャペロンとして、4−フェニル酪酸ナトリウム(Sigma-Aldrich, Cat.# SML0309, 以下「4PBA」と略記する)およびトリメチルアミン−N−オキシド二水和物(Sigma-Aldrich, Cat.# 317594, 以下「TMAO」と略記する)を用いた。4PBAは5mM、1mMおよび0.2mMの各濃度で培地に添加し、TMAOは100mM、50mMおよび5mMの各濃度で培地に添加した。
小胞体内のI型コラーゲンの蓄積を定量化するために蛍光免疫染色を行った。I型コラーゲンに対する一次抗体として抗I型コラーゲン抗体(Abcam, Cat.# ab34710)を用い、小胞体マーカーに対する一次抗体として抗PDI(protein disulfide isomerase)モノクローナル抗体(Enzo, Cat.# ADI-SPA-891)を用いた。二次抗体としてAnti−Rabbit IgG(Jackson Immunoresearch; 711-485-152)およびAnti−Mouse IgG(Jackson Immunoresearch; 715-505-151)を用いた。
細胞を2日間培養した後に、4%パラホルムアルデヒドで10分間、続いて冷メタノールで1分間インキュベートして細胞を固定し、ブロッキングバッファー(PBS, 1% BSA, 10% FBS, 0.3 M glycine, 0.1% Tween 20)を添加して1時間室温でインキュベートした。その後、抗コラーゲンI型抗体および抗PDIクローナル抗体を、ブロッキングバッファーでそれぞれ1:100および1:200に希釈した一次抗体溶液で、一晩4℃でインキュベートした。続いて各二次抗体をブロッキングバッファーでそれぞれ1:500に希釈した二次抗体溶液で、1時間室温でインキュベートした。
蛍光染色した細胞を、In Cell Analyzer 6000(GE Healthcare)で撮影し、In Cell Developer Toolbox(GE Healthcare)を用いて小胞体マーカーと共局在を示すI型コラーゲンの蛍光強度を測定した。
結果を図1に示した。小胞体内I型コラーゲンの蓄積量は、正常細胞(normal)のケミカルシャペロン非添加群のI型コラーゲンの蛍光強度を1とし、各群のI型コラーゲンの蛍光強度の相対値で示した。骨形成不全症患者細胞(OI)のケミカルシャペロン非添加群では、正常細胞の1.6倍を超えるI型コラーゲンが小胞体内に蓄積していた。4PBAを添加した骨形成不全症患者細胞では、濃度依存的にI型コラーゲンの小胞体内蓄積量を減少させ、5mM群では正常細胞と同レベルにまで減少した。また、4PBAの正常細胞に対する影響は少なかった。一方、骨形成不全症患者細胞にTMAOを添加した群でも50mMおよび5mMの濃度において、I型コラーゲンの小胞体内蓄積量の減少が認められたが、4PBAのように顕著な効果は認められなかった。この結果は、骨形成不全症患者細胞における小胞体内I型コラーゲン蓄積量の減少(正常化)は、単にケミカルシャペロンによる高次構造の修復のみでは十分でなく、4PBAによる何らかの別の作用が寄与しているものと考えられる。
Claims (5)
- 変異を有するI型コラーゲンの小胞体内過剰蓄積正常化剤であって、4−フェニル酪酸またはその薬学的に許容される塩を有効成分とすることを特徴とする剤。
- 4−フェニル酪酸の薬学的に許容される塩が4−フェニル酪酸ナトリウムである請求項1に記載の剤。
- 請求項1または2に記載の剤を含有する、I型コラーゲンの3重らせん構造を構成している部位に存在するグリシンが別のアミノ酸に置換された変異を有する骨形成不全症の治療用医薬。
- 前記グリシンがI型コラーゲンのα1鎖のグリシンである請求項3に記載の医薬。
- 前記グリシンがI型コラーゲンのα1鎖の821番目のグリシンである請求項3に記載の医薬。
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