TW202237075A - 抑制小兒近視進展用點眼劑及小兒近視進展抑制劑之篩選方法 - Google Patents
抑制小兒近視進展用點眼劑及小兒近視進展抑制劑之篩選方法 Download PDFInfo
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Abstract
本發明課題為提供一種探索抑制PERK途徑及/或ATF6途徑的成分之篩選方法;及藉由該篩選方法得到不會阻礙小兒正常眼球成長(正視化)並抑制近視進展的有效成分;包含該有效成分的點眼劑及組成物。
解決手段:藉由一種抑制小兒近視進展用點眼劑來解決上述課題,其係含有PERK(PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑作為有效成分。藉由一種小兒近視進展抑制劑之篩選方法來解決上述課題,其係包含:使來自眼睛的細胞接觸候選物質的步驟;及以前述細胞中的PERK及/或ATF6之訊息傳遞鏈的蛋白質及/或基因的變化為指標來選擇候選物質的步驟。
Description
本發明關於一種為了抑制小兒近視進展所使用的點眼劑及小兒近視進展抑制劑之篩選方法。進一步詳細而言,本發明關於一種有效成分,藉由抑制小兒近視進展原因基因的ATF6及/或PERK,不會抑制小兒的正常眼球的成長(將「小兒的正常眼球成長」稱為「正視化」)所必要的生理性的眼軸伸長,可僅抑制造成近視的疾病性的眼軸伸長;包含該有效成分之點眼劑,及該有效成分之篩選方法。
根據近視及重度近視相關的最新研究,預測世界上近視人口顯著增加,預測在2050年近視會達到約50億人,重度近視會達到約10億人(參考非專利文獻1)。
另外,依據2019年日本慶應義塾大學醫學部的疫學調查,判明了東京都內小學生689人的近視罹患率為76.5%,尤其在小學1年級時,近視罹患率已經超過60%。另外,同樣在東京都內中學生727人的近視罹患率為94.9%,無論哪個學年都得到超過90%的結果(參考非專利文獻2)。這已高於東亞其他國家所報告的罹患率,小兒近視在日本可說是達到極嚴重的程度。
人的眼睛在剛誕生時為遠視,在成長期(到8歲),因為前後方向的眼軸伸長而讓光軸伸長,遠視的程度會變小,若進入學齡期,則會成為適當的眼軸長而正視化。將其稱為「生理性的眼軸伸長」,該生理性的眼軸伸長若因為某些原因而受到損害,則會因為眼軸伸長不足而造成遠視,使小兒的生活品質(Quality of Life)顯著惡化。另一方面,將正視化後眼軸伸長還沒有停止,8歲以後眼軸長過度伸長稱為「疾病性的眼軸伸長」,這是小兒近視進展的原因,所以,近視會在8歲以後的學齡期急劇惡化,一旦伸長之後,眼軸長度無法復原(參考非專利文獻3)。
為了抑制小兒近視進展,必須抑制此過度眼軸伸長(疾病性的眼軸伸長),然而若連生理性的眼軸伸長也抑制,則雖然不會變成近視,但是會造成遠視而本末倒置。所以,在正確的抑制小兒近視進展策略之中,必須讓抑制疾病性的眼軸伸長以及不會抑制生理性的眼軸伸長這兩個相反的作用同時成立。
[先前技術文獻]
[專利文獻]
專利文獻1:國際公開WO2018/164113
[非專利文獻]
非專利文獻1:Brien A Holden, et. al., “Global prevalence of myopia and high myopia ando temporal trends from 2000 through 2050”, Ophthalmology, Vol.123, Number 5, P.1036-1042 (May 2016).
非專利文獻2:「中小學生近視增加傾向的警鐘」、日本慶應義塾大學醫學部、2019年8月19日新聞稿(https://oklens.co.jp/new/2019/08/21/).
非專利文獻3:不二門尚、「日本眼科學會專門醫制度生涯教育講座 總說54 小兒近視的進行防止」、日眼會誌、117卷、4號、397頁~406頁(平成25年4月10日).
非專利文獻4:Jiang, X., et. al., A highly efficient murine model of experimental myopia. Scientific reports 8, 2026, doi:10. 1038/s41598-018-20272-w(2018).
非專利文獻5:Mori, K., et. al., Oral crocetin administration suppressed refractive shift and axial elongation in a murine model of lens-induced myopia. Scientific reports 9, 295, doi:10. 1038/s41598-018-36576-w(2019)
非專利文獻6:Xiangtian Zbou, et al., The Development of the Refractive Status and Ocular Growth in C57BL6 Mice. Investigative Ophthalmology & Visual Science, December 2008, Vol.49, No.12.
[發明所欲解決的課題]
近年來,關於導致小兒近視進展(疾病性的眼軸伸長)的因子逐漸明朗。本發明人等針對該因子群潛心研究,結果發現,內質網中異常蛋白質的未摺疊蛋白反應的基因(內質網壓力反應基因)與疾病性的眼軸伸長有密切關聯(參考專利文獻1)。該基因群已知有PERK(PKR-like endoplasmic reticulum kinase)、ATF6(Activating transcription factor 6)、IRE1(Inositol requiring 1)三種,然而應該抑制哪一種基因途徑,或者是否抑制全部的途徑即可等等,各途徑詳細的貢獻程度不明。這些基因途徑的抑制如果不足,則無法達成疾病性的眼軸伸長的充分抑制,或者,如果過度抑制,則可能會連帶抑制生理性的眼軸伸長,因此同時發生疾病性的眼軸伸長與生理性的眼軸伸長的小兒近視進展,其抑制被認為是極為困難。
[用於解決課題的手段]
本發明人等檢討了內質網壓力反應基因(PERK、ATF6、IRE1)的訊息傳遞鏈(途徑)與疾病性的眼軸伸長的關聯度、各途徑的抑制對於抑制眼軸伸長的貢獻程度、或組合抑制的情況的相乘效果。結果發現,藉由抑制PERK途徑及/或ATF6途徑,疾病性的眼軸伸長抑制效果會提高。另外還發現,選擇性地抑制至少ATF6途徑,對於抑制小兒近視進展而言是重要的,藉由抑制PERK途徑及ATF6途徑這兩個途徑,可充分抑制小兒的疾病性的眼軸伸長(近視進展),同時不會抑制生理性的眼軸伸長(正視化)。
本發明之目的,在於提供一種探索抑制PERK途徑及/或ATF6途徑的成分之篩選方法。另外還有藉由該篩選方法,得到不會阻礙小兒的正常眼球成長(正視化),且抑制近視進展的有效成分,包含該有效成分的點眼劑。此外還提供一種方法,針對被認為對近視有效的各種成分,檢驗該成分對疾病性的眼軸伸長與生理性的眼軸伸長同時進行的小兒來說是否安全,亦即是否伸長不足造成遠視或者不會過度伸長造成近視。
亦即,本發明為:
[1] 一種抑制小兒近視進展用點眼劑,其係含有PERK(PKR-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑作為有效成分。
[2] 如上述[1]之點眼劑,其中前述阻礙劑係選自由苯基酪酸及其藥理學所容許的鹽所成的群組中的至少一種。
[3] 如上述[1]或[2]之點眼劑,其中前述阻礙劑為苯基酪酸鈉。
[4] 如上述[1]~[3]中任一項之點眼劑,其中前述阻礙劑的含量,相對於點眼劑總量為0.01~5質量%。
[5] 如上述[1]~[4]中任一項之點眼劑,其中前述抑制小兒近視進展不會抑制生理性的眼軸伸長。
[6] 如上述[1]~[5]中任一項之點眼劑,其中前述抑制小兒近視進展會抑制疾病性的眼軸伸長。
[7] 一種小兒近視進展抑制劑之篩選方法,其係包含:使來自眼睛的細胞接觸候選物質的步驟;及以前述細胞中的PERK及/或ATF6之訊息傳遞鏈的蛋白質及/或基因的變化為指標來選擇候選物質的步驟。
[發明之效果]
依據本發明,可提供一種探索抑制PERK及/或ATF6之訊息傳遞鏈的成分之篩選方法。藉由這樣的篩選方法,可提供不會阻礙小兒的生理性的眼軸伸長(正視化)並且會抑制近視進展的有效成分,並可提供包含該有效成分的點眼劑及組成物。
以下詳細說明本發明。本發明並不受以下的實施形態及實驗例限定,在囊括了本發明的要旨的範圍內,包含各種變形例或應用例。
[抑制小兒近視進展用點眼劑]
本發明所關連的抑制小兒近視進展用點眼劑,含有PERK(PKR-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑作為有效成分。
在本說明書之中,PERK途徑及/或ATF6途徑的阻礙劑,是指對於PERK之訊息傳遞鏈(PERK途徑)及/或ATF6之訊息傳遞鏈(ATF6途徑)具有阻礙效果的物質。對於這些訊息傳遞鏈的阻礙效果,如後述實施例般,可藉由周知的方法,以與這些訊息傳遞鏈相關的基因及/或蛋白質的變化為指標來評估。
(PERK途徑及/或ATF6途徑的阻礙劑)
如上述般,關於小兒近視進展(疾病性的眼軸伸長)的因子,與內質網中異常蛋白質的未摺疊蛋白反應的基因途徑會和疾病性的眼軸伸長有關聯。該基因途徑,已知有PERK途徑、ATF6途徑及IRE1途徑三種,如後述實驗例所示般,新發現了至少抑制ATF6途徑對於抑制近視而言是必須的。另外還新發現了在這三種途徑之中,藉由抑制PERK途徑與ATF6途徑,抑制小兒近視進展效果會更加提高。還確認了在僅抑制PERK途徑或ATF6途徑的任一者的情況,會有代償性地活化另一個途徑的情形。所以,在一個實施形態之中,對於PERK途徑與ATF6途徑的任一者皆具有阻礙效果的物質,可成為抑制小兒近視進展的有效成分,然而並不受限定。
亦即,以與PERK及/或ATF6的訊息傳達相關的基因或蛋白質為標的,使其減少的化合物、或降低PERK途徑及/或ATF6途徑的蛋白質表現的反義寡核苷酸、siRNA等的核酸,可作為抑制小兒近視進展的有效成分來摻合至點眼劑。
在本說明書之中,PERK途徑或ATF6途徑的阻礙劑,是指對於內質網中的PERK的訊息傳遞鏈或ATF6的訊息傳遞鏈具有阻礙效果的物質。對這些訊息傳遞鏈的阻礙效果,可藉由後述實驗例所記載的方法,或藉由周知的方法,以與這些訊息傳遞鏈有關聯的基因及/或蛋白質的變化作為指標來評估。
在評估PERK的訊息傳遞鏈相關因子的基因表現或蛋白質表現時,可藉由與不添加候選物質的控制組作比較,該因子的表現因為候選物質至少變動1%來進行評估。
另外,在評估與ATF6之訊息傳遞鏈相關的因子的基因表現或蛋白質表現時,可藉由與不添加候選物質的控制組作比較,該因子的表現因為候選物質至少變動1%來進行評估。
PERK是內質網跨膜型激酶,與其訊息傳達相關的因子可列舉例如eIF2α(eukaryotic initiation factor 2α)、ATF4(Activating transcription factor 4)、CHOP (C/EBP homologous protein)、GADD34(growth arrest DNA and damage protein 34)等。
另外,ATF6是屬於CREB/ATF家族的膜結合型轉錄因子,與其訊息傳達相關的因子可列舉例如BiP (Binding immunoglobulin protein,亦被稱為「GRP78」)、Txndc12(thioredoxin domain containing 12,亦被稱為「ERp18」)、S1P(site-1 protease)、S2P(site-2 protease)等。
在後述實驗例之中,藉由篩選可抑制PERK途徑與ATF6途徑兩者的成分,發現了選自由苯基酪酸、牛磺熊去氧膽酸及其藥理學所容許的鹽所成的群組中的至少一種。但是,不限於這些,新鑑定出來至少抑制ATF6途徑的成分、或新鑑定出來抑制PERK途徑與ATF6途徑的成分也能夠使用。ATF6途徑的阻礙劑並不受限定,從在點眼劑中的溶解性的觀點看來,以苯基酪酸鈉為佳。如後述實驗例所記載般,如果是苯基酪酸鈉,則除了ATF6途徑之外,還可阻礙PERK途徑,故為適合。PERK途徑及/或ATF6途徑的阻礙劑,可藉由周知的方法合成來使用,或購買市售品來使用。
在本說明書之中,「藥學可容許的鹽」並未受到特別限制,具體而言,可列舉有機酸鹽、無機酸鹽、有機鹼、或無機鹼。有機酸鹽,可列舉例如醋酸鹽、三氟醋酸鹽、酪酸鹽、棕櫚酸鹽、硬脂酸鹽等的單羧酸鹽;富馬酸鹽、馬來酸鹽、琥珀酸鹽、丙二酸鹽等的多價羧酸鹽;乳酸鹽、酒石酸鹽、檸檬酸鹽等的羥基羧酸鹽;甲烷磺酸鹽、甲苯磺酸鹽、甲苯磺酸鹽等的有機磺酸鹽。無機酸鹽,可列舉例如鹽酸鹽、硫酸鹽、硝酸鹽、氫溴酸鹽、磷酸鹽。有機鹼的鹽,可列舉例如甲基胺、三乙基胺、三乙醇胺、二乙醇胺、嗎啉、哌嗪、吡咯啶、三吡啶、甲吡啶、乙二胺等的有機胺的鹽。無機鹼的鹽,可列舉例如銨鹽;鈉或鉀等鹼金屬、鈣或鎂等的鹼土類金屬、鋁等的金屬的鹽等的各種鹽。這些鹽可單獨使用一種或將兩種以上任意組合使用。「藥學所容許的鹽」亦可包括鹽的溶劑合物或水合物。
PERK途徑及/或ATF6途徑的阻礙劑的含量,可依照用法、用量、添加劑的種類等適當地變更。例如相對於點眼劑總量(是指總質量,在本說明書中皆相同),以0.01質量%以上為佳,0.05質量%以上為較佳,0.1質量%以上為更佳,0.2質量%以上為特佳。另外,PERK途徑及/或ATF6途徑的阻礙劑的含量,例如相對於點眼劑總量,以5質量%以下為佳,4質量%以下為較佳,3質量%以下為更佳,2質量%以下為特佳。另外,PERK途徑及/或ATF6途徑的阻礙劑的含量,例如相對於點眼劑總量,以0.01~5質量%為佳,0.05~4質量%為較佳,0.1~3質量%為更佳,0.2~2質量%為特佳。
在使用選自由苯基酪酸及其藥理學所容許的鹽所成的群組中的至少一種作為PERK途徑及/或ATF6途徑的阻礙劑的情況,其含量,例如相對於點眼劑總量,以0.01~5質量%為佳,0.05~4質量%為較佳,0.1~3質量%為更佳,0.2~2質量%為特佳。
[用途]
本發明所關連的點眼劑可使用於抑制小兒近視進展。在本說明書中,小兒是指7歲以上未滿15歲的兒童。眼睛屈光的程度,在出生後為輕度的遠視,到學齡期眼軸會伸長至大致為正視。
從出生後到2歲左右,眼軸長會急速伸長,後來會徐緩地伸長。這種隨著成長而正視化的眼軸伸長,稱為「生理性的眼軸伸長」,是眼睛正常成長所不可或缺的現象。但是在學齡期以後眼軸長繼續伸長,會導致近視惡化,因此被認為是「疾病性的眼軸伸長」。例如在疾病性的眼軸伸長的情況,成人眼睛的眼軸長伸長1mm,會導致近視度增加約3.0D,而且眼軸伸長不會復原。
所以,在抑制小兒近視進展時,需要不抑制生理性的眼軸伸長(正視化),只抑制疾病性的眼軸伸長(近視進展)。在後述實驗例之中,新發現了至少抑制ATF6途徑對於抑制近視而言是必須的。在僅抑制PERK途徑或ATF6途徑的任一者的情況,也確認了會有代償性地活化另一個途徑的情況。所以,在一個實施形態之中,發現了藉由抑制PERK途徑與ATF6途徑的兩者,疾病性的眼軸伸長抑制效果會相乘地提高,然而並不受限定。根據這種機制,不會抑制生理性的眼軸伸長(正視化),能夠抑制小兒近視進展。
(劑形)
本發明所關連的組成物可作為點眼劑來使用。在本發明中,抑制小兒近視進展用點眼劑的劑形並未受到限定,可列舉例如水性點眼劑、用時溶解點眼劑、懸浮性點眼劑、油性點眼劑、眼軟膏劑等。其中,從顯著發揮本發明的效果的觀點看來,以水性點眼劑為佳。
在點眼劑中,除了上述成分之外,還可摻合其他有效成分(藥理活性成分、生理活性成分等)。這種成分的種類並不受特別限制,可列舉例如解除充血成分、眼肌調節藥成分、抗發炎藥成分、收斂藥成分、抗組織胺藥成分、抗過敏藥成分、維生素類、胺基酸類、抗菌藥成分、糖類、高分子化合物或其衍生物、纖維素或其衍生物、局部麻醉藥成分等。
在點眼劑中,進一步在不損及本發明效果的範圍,可因應其用途或形態,依照常法適當地選擇各種成分或添加物,可併用而含有一種或兩種以上。這些成分或添加物,可列舉例如一般使用於調製液劑等的擔體、香料或清涼化劑、防腐劑、殺菌劑或抗菌劑、pH調節劑、螯合劑、安定化劑、等張化劑、緩衝劑、黏稠化劑等的各種添加劑。以下例示點眼劑所使用的代表性的成分,然而不受其限定。
擔體可列舉例如水、含水乙醇等的水性溶劑。此外,在各種成分不易溶於水性溶劑的情況,亦可使用可溶化劑。可溶化劑,可列舉例如聚氧伸乙基硬化蓖麻油、聚乙二醇40硬脂酸酯、聚維酮、聚山梨醇酯80等。
香料或清涼化劑,可列舉例如萜烯類(具體而言,茴香腦、丁香酚、樟腦、香葉醇、桉油醇、冰片、薄荷醇、薴烯、龍腦等,這些可為d體、l體或dl體之任一者)、精油(茴香油、冷薄荷油、肉桂油、綠薄荷油、薄荷水、薄荷油、辣薄荷油、佛手柑油、桉樹油、玫瑰油等)等。
防腐劑、殺菌劑或抗菌劑,可列舉例如泊利氯銨、鹽酸烷基二胺乙基甘胺酸、安息香酸鈉、乙醇、苯扎氯銨、芐索氯銨、氯己定葡萄糖酸鹽、氯丁醇、山梨酸、山梨酸鉀、脫水乙酸鈉、對羥基安息香酸甲酯、對羥基安息香酸乙酯、對羥基安息香酸丙酯、對羥基安息香酸丁酯、硫酸羥基喹啉、苯乙醇、苄醇、雙胍化合物(具體而言,聚六亞甲基雙胍或其鹽酸鹽等)、Glokill(Rhodia公司製的商品)等。
pH調節劑,可列舉例如鹽酸、氫氧化鈉、氫氧化鉀、氫氧化鈣、氫氧化鎂、三乙醇胺、單乙醇胺、二異丙醇胺、硫酸、磷酸等。
螯合劑,可列舉例如抗壞血酸、依地酸四鈉、依地酸鈉、檸檬酸等。
安定化劑,可列舉例如依地酸鈉水合物、聚維酮、聚山梨醇酯80、二丁基羥基甲苯、胺丁三醇、甲醛次硫酸氫鈉(吊白塊)、生育酚、焦亞硫酸鈉、單乙醇胺、單硬脂酸鋁、單硬脂酸甘油等。
等張化劑,可列舉例如氯化鉀、氯化鈉、濃甘油、葡萄糖、D-甘露醇等。
緩衝劑,可列舉例如檸檬酸鈉水合物、醋酸鈉水合物、碳酸氫鈉、胺丁三醇、硼酸、硼砂、磷酸氫鈉水合物、磷酸二氫鈉等。
黏稠化劑,可列舉例如羧乙烯基聚合物、聚維酮、聚乙烯醇(部分皂化物)、羥乙基纖維素、羥丙基甲基纖維素、甲基纖維素、甘油等。
在本發明所關連的點眼劑之中,可在能夠期待本發明的效果或不阻礙本發明的效果的範圍內摻合添加劑。其含量並未受到特別限定,相對於點眼劑總量,以0.001~1質量%左右為佳。
點眼劑的pH只要定在3~10即可,從使用感的觀點看來,以4~9為佳,從使用感的觀點看來,以5~8.5為較佳。
收納本發明所關連的點眼劑的容器,可使用周知的點眼容器,而沒有限制。點眼容器,通常可採用能將點眼劑滴入眼睛的形狀,例如具備滴嘴,滴嘴前端具備容器開口的形狀的容器。另外,點眼容器,可為在容器上安裝另外成形的滴嘴的構造的容器,以及滴嘴部(液體的流出部)與容器本體一體成型的構造的容器(例如一次性拋棄型的點眼容器等)之任一者。
點眼容器通常只要採用塑膠容器即可。塑膠容器的構成材料並未受到特別限制,可列舉例如聚對苯二甲酸乙二酯、聚芳酯、聚萘二甲酸乙二酯、聚碳酸酯、聚乙烯、聚丙烯、聚醯亞胺的任一種,其共聚物、或其兩種以上的混合物。尤其,從擠出的力道等方面容易發揮出本發明的效果的觀點看來,以聚對苯二甲酸乙二酯、聚芳酯、聚萘二甲酸乙二酯或其共聚物、或其兩種以上的混合物為佳。
點眼劑可填充至以這種材料為主材料的透明容器(具備不妨礙到觀察異物的程度的透明性之容器),或可填充至遮光容器。遮光可藉由例如在透明容器材料中添加著色劑來進行,或可藉由以收縮薄膜或外箱等來包覆容器來遮光。另外,為了讓擠出的力道等方面更容易地發揮出本發明的效果,容器的容量以0.5~50mL左右為佳,3~20mL左右為較佳。
另外,關於被設置在點眼容器的滴嘴,其構造或構成材料並不受特別限制。滴嘴的構造,只要是點眼容器的滴嘴一般可採用的構造即可。另外,關於滴嘴的構成材料,可例示例如與上述塑膠容器的構成材料同樣的材料。從讓點眼劑的斷液更加良好,以及抑制滴入量的變動的觀點看來,以包含聚乙烯或聚丙烯作為構成材料的滴嘴為適合。聚乙烯的種類,可列舉高密度聚乙烯、低密度聚乙烯等,尤其以包含低密度聚乙烯作為構成材料的滴嘴為適合。
(點眼劑的製造方法)
本發明所關連的點眼劑,可藉由業界人士慣用或周知的方法來調製。例如,只要藉由使各成分分散於水等的擔體之後,如果有必要則添加可溶化劑,並因應必要加熱,使用均質機等來使其均勻化、溶解或乳化,以pH調整劑調整pH來調製即可。另外,製劑的滅菌方法,可選擇電子束滅菌、高壓滅菌釜滅菌、過濾滅菌等的方法。
(使用方法)
本發明所關連的點眼劑的用法及用量,會依照患者的症狀等而變動,通常1天只要約點眼1~6次,1次約1~2滴即可。
本發明所關連的點眼劑可對小兒適用。在使用含有選自由苯基酪酸及其藥理學所容許的鹽所成的群組中的至少一種作為PERK途徑及/或ATF6途徑的阻礙劑的點眼劑的情況,例如可將點眼劑以1天1~2次、1次1~2滴來點眼,以1天1次、1次1滴來點眼為佳,然而並不受限定。
另外,從顯著發揮本發明的效果的觀點看來,本發明所關連的點眼劑,可在例如午睡前、就寢前等的活動不活躍的時間帶對小兒使用。
[小兒近視進展抑制劑的篩選方法]
在本發明中,小兒近視進展抑制劑的篩選方法,包含:使來自眼睛的細胞接觸候選物質的步驟;以前述細胞中的PERK及/或ATF6的訊息傳遞鏈的蛋白質及/或基因的變化為指標來選擇候選物質的步驟。例如,在候選物質的存在下或不存在下,與細胞接觸,並且測定候選物質造成的PERK及/或ATF6的訊息傳遞鏈的蛋白質及/或基因的變化,加以比較,可進行候選物質的篩選,然而並不受限定。
來自眼睛的細胞不受限定,從顯著發揮本發明的效果的觀點看來,以鞏膜的細胞為佳,鞏膜纖維母細胞為較佳。
來自眼睛的細胞,以來自誘導近視的動物模型的細胞為佳,然而並不受限定。這種近視誘導模型可利用周知的動物模型。
近視誘導模型,可列舉配戴負鏡片來誘導近視的動物模型、藉由投予近視誘導劑來誘導近視的動物模型等,然而並不受限定。
這種負鏡片可利用屈光度-20~-40(D)的鏡片,宜為屈光度-25~-35(D)的鏡片。負鏡片的配戴方法可使用周知的方法,可列舉使用固定器具將負鏡片固定於動物的眼前等,然而並不受限定。
負鏡片的配戴期間,可定為例如至少1週,以2週以上為佳,3週以上為較佳。
另外,近視誘導劑可利用周知的物質,例如作為近視誘導劑,如後述實驗例的評估所述般,可使用衣黴素、毒胡蘿蔔素等。另外,近視誘導劑,亦可與PERK途徑的活化劑或ATF6途徑的活化劑組合使用。PERK途徑的活化劑可列舉CCT020312等,ATF6途徑的活化劑可列舉AA147等,可將其單劑投予或混合投予,以將其混合投予為佳。
這種近視誘導劑不受限定,從與鞏膜等的眼睛細胞發生作用的觀點看來,例如可製成注射劑或點眼劑來投予,以製成點眼劑來投予為佳。在使用衣黴素作為點眼劑的情況,可定為例如10~100μg/mL,以20~80μg/mL為佳,40~60μg/mL為較佳。
在使用毒胡蘿蔔素作為點眼劑的情況,可定為例如1~100μM,以2~60μM為佳,5~30μM為較佳。
關於對動物誘導近視的開始時期,從製作出預設可適用於小兒的動物模型的觀點看來,以使用幼齡動物為佳。在小鼠的情況,以從離乳時期開始配戴負鏡片為佳,3週齡小鼠為較佳,然而並不受限定。在C57BL6等的小鼠的情況,從3週齡到6週齡會發生生理性的眼軸伸長。所以,由3週齡開始誘導近視,除了生理性的眼軸伸長之外,還可促進眼軸過度伸長,因此可讓疾病性的眼軸伸長發生。例如在對於3週齡小鼠進行近視誘導前後或進行近視誘導期間適用候選物質為佳。根據該手段,可評估候選物質對生理性的眼軸伸長或疾病性的眼軸伸長造成的影響。另外,在動物使用白色來亨雞的情況,從製作出預設可適用於小兒的動物模型的觀點看來,以使用例如5天齡的白色來亨雞幼鳥為佳。
使候選物質接觸來自眼睛的細胞的步驟,以藉由口服、腹腔內注射或點眼來投予該候選物質為佳,藉由點眼來投予為較佳,然而並不受限定。例如以鞏膜的細胞來進行評估的情況,可讓點眼劑中含有候選物質來投予。
在測定候選物質造成的PERK及/或ATF6的訊息傳遞鏈的蛋白質及/或基因的變化的步驟中,可使用周知的評估方法。基因的表現或蛋白質的表現或分泌,可藉由微陣列、實時PCR法、PCR法、西方墨點法、ELISA法、免疫組織染色等的周知方法來測定,然而並不受限定。
例如在測定PERK或ATF6之訊息傳遞鏈的基因變化的情況,可使用周知的RNA萃取方法,由培養細胞萃取出RNA,供定量分析mRNA表現的步驟使用。
定量分析mRNA表現的步驟不受限定,以使用實時PCR法為佳。以實時PCR法所測定的標記,可將以上在(PERK途徑及ATF6途徑的阻礙劑)的項目所述的訊息傳達相關的因子定為測定項目。
與PERK途徑相關的因子,可列舉例如CHOP、ATF4、GADD34等。
與ATF6途徑相關的因子,可列舉例如GRP78、GRP94、PDI、Cnex、HYOU、ERdj3等。
在PERK及/或ATF6之訊息傳遞鏈的蛋白質及/或基因的表現因為候選物質而受到抑制的情況,可選定該候選物質作為PERK途徑及/或ATF6途徑的阻礙劑,作為小兒近視進展抑制劑來使用。
本發明可為以下的態樣。
一種抑制小兒近視進展用點眼劑,其係含有PERK (PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6 (Activating transcription factor 6)途徑的阻礙劑作為有效成分;
一種含有PERK(PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑作為有效成分之點眼劑,其係在抑制小兒近視進展中使用;
PERK(PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑在製造抑制小兒近視進展用點眼劑的方面的使用;
一種抑制小兒近視進展方法,其係包含使人攝取有效量的PERK(PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑;
如上述所記載的點眼劑、使用、或方法,其中包含前述阻礙劑,至少選擇性地抑制ATF6途徑;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑為PERK途徑及ATF6途徑的兩途徑的阻礙劑;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑為選自由苯基酪酸及其藥理學所容許的鹽所成的群組中的至少一種;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑為苯基酪酸鈉;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑的含量,相對於點眼劑總量,為0.01~5質量%;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑的含量,相對於點眼劑總量為0.1~3質量%;
如上述所記載的點眼劑、使用、或方法,其中前述阻礙劑的含量,相對於點眼劑總量為0.2~2質量%;
如上述所記載的點眼劑、使用、或方法,其中前述抑制小兒近視進展不會抑制生理性的眼軸伸長;
如上述所記載的點眼劑、使用、或方法,其中前述抑制小兒近視進展會抑制疾病性的眼軸伸長;
如上述所記載的點眼劑、使用、或方法,其中前述小兒包括7歲以上未滿15歲的兒童;
如上述所記載的點眼劑、使用、或方法,其中前述點眼劑為水性點眼劑;
如上述所記載的點眼劑、使用、或方法,其中前述點眼劑係以1天1~2次的點眼來使用;
如上述所記載的點眼劑、使用、或方法,其中前述點眼劑係以1天1~2次的點眼來使用;
如上述所記載的點眼劑、使用、或方法,其中前述點眼劑係在午睡前,或就寢前使用;
一種小兒近視進展抑制劑之篩選方法,其係包含:使來自眼睛的細胞接觸候選物質的步驟;及以前述細胞中的PERK及/或ATF6之訊息傳遞鏈的蛋白質及/或基因的變化為指標來選擇候選物質的步驟;
如上述所記載的篩選方法,其中前述來自眼睛的細胞係來自誘導近視的動物模型的細胞;
如上述所記載的篩選方法,其中前述動物模型係配戴負鏡片來誘導近視的動物模型,或藉由投予近視誘導劑來誘導近視的動物模型;
如上述所記載的篩選方法,其中前述負鏡片為屈光度-20~-40(D)之鏡片;
如上述所記載的篩選方法,其中前述負鏡片的配戴期間為至少1週;
如上述所記載的篩選方法,其中前述近視誘導劑包含衣黴素及/或毒胡蘿蔔素;
如上述所記載的篩選方法,其中前述衣黴素的點眼投予的情況的濃度為10~100μg/mL;
如上述所記載的篩選方法,其中前述毒胡蘿蔔素的點眼投予的情況的濃度為1~100μM;
如上述所記載的篩選方法,其中前述動物模型係在離乳時期開始配戴負鏡片;
如上述所記載的篩選方法,其中使前述來自眼睛的細胞接觸候選物質的步驟包含藉由口服,腹腔內注射或點眼來投予前述候選物質;
如上述所記載的篩選方法,其中包含在PERK及/或ATF6之訊息傳遞鏈之蛋白質及/或基因的表現因為候選物質而受到抑制的情況,選擇該候選物質作為小兒近視進展抑制劑;
如上述所記載的篩選方法,其中包含在PERK及ATF6的訊息傳遞鏈的蛋白質及/或基因的表現因為候選物質而受到抑制的情況,選擇該候選物質作為小兒近視進展抑制劑。
[實施例]
以下列舉實驗結果對本發明作具體說明。
[實驗方法]
本實驗中所有的動物實驗皆受到日本慶應義塾大學動物實驗委員會的承認,遵守慶應義塾大學動物實驗相關的設施準則、眼科・視覺研究時的動物使用相關的ARVO聲明、動物研究:研究時的動物使用相關的in vivo實驗報告(ARRIVE)準則。
(近視誘導幼齡小鼠的特徵)
如非專利文獻3所記載般,人的眼睛在剛出生時為遠視,然後眼軸會伸長(亦即近視化),在學齡期(8歲時)正視化。另外,如非專利文獻6所記載般,小鼠(C57BL6)3至6週齡的期間,眼軸也會隨著成長而伸長。所以,此近視誘導幼齡小鼠,從近視進展動態的觀點看來,相當於人類8歲前後,這實質上相當於幼兒、小兒(學齡期)。藉由使用此動物模型,可解釋人類小兒近視進展的機制,能夠篩選出小兒近視進展治療劑。
將配戴負鏡片誘導軸性近視的機構模式地表示於圖1(a)。正視是指進入眼睛的平行光線在視網膜上成像,因此清楚看到影像的狀態。另一方面,軸性近視是指眼軸長變長,因此進入眼睛的平行光線在視網膜的前方成像,而無法看清楚的狀態。包括人類在內,動物的眼睛會隨著成長變大。若讓幼齡的小鼠配戴負鏡片,則眼軸會伸長至配戴負鏡片時成像的位置,亦即配戴負鏡片時成為清楚看見的狀態。結果,眼軸會伸長,可製作出與軸性近視同樣的眼睛狀態。
(近視誘導幼齡小鼠的製作)
具體而言,如以下所述般,製作出近視誘導幼齡小鼠。此外,近視誘導、眼軸長及屈光度的測量,是依照與非專利文獻4、5同樣的方法來進行。首先,在12小時明暗循環的溫度控制無塵室中將雄性C57BL6J小鼠收容於標準透明籠子。讓動物自由攝取標準飼料與經過高壓蒸氣滅菌的自來水。將剛離乳的3週齡小鼠以Domitor(日本全藥工業股份有限公司)、Vetorphale(Meiji Seika Pharma股份有限公司)、咪達唑侖(Sandoz股份有限公司)三種混合麻醉藥來進行麻醉,以剪刀使頭蓋骨露出。如圖1(b)所示般,在頭蓋骨上豎立支柱,並以牙科用黏合劑(Super-Bond,Sun Medical股份有限公司)來固定。在支柱上設置了螺牙,可將後述調節器具以螺帽來固定。
為了誘導近視,在右眼(近視誘導眼)配戴屈光度-30(diopter,D)的負鏡片(RAINBOW CONTACT,RAINBOW OPTICAL研究所股份有限公司),在左眼(控制組眼睛)配戴0D的鏡片或僅配戴鏡框以作為控制組。在讓小鼠配戴鏡片時,在鏡片下部的鏡框部接著了往側向突出的護具,讓鏡片不會因為小鼠的前腳等而刮傷。藉由護具,小鼠無法接觸到鏡片,不會刮傷鏡片。此處的護具是使用接著於鏡框部而一體化的護具,只要不會因為小鼠的行動而刮傷鏡片即可,沒有必要與鏡片一體化。例如,可為如遭受外傷的動物所配戴的伊莉莎白頸圈般的形狀的護具。
在鏡片上方的鏡框部,接著有用來依照小鼠的成長調節所配戴的鏡片的寬度或角度的調節器具。調節器具彎折成「く」字形,一端接著於鏡片,另一端設置長孔,可安裝於豎立在頭部的支柱。藉由讓支柱通過長孔,並以螺帽拴緊,可不壓迫小鼠兩眼周圍而與皮膚密著地固定。藉由由支柱、螺帽、調節器具3個物件所構成的調節機構,可依照小鼠的成長來調節寬度、角度,將鏡片調整至小鼠眼前的位置。另外,鏡片還可取下,因此可測量眼軸長、屈光度的逐時變化。
(眼軸伸長與屈光度的測量)
控制組的眼睛僅配戴鏡框,近視誘導眼配戴-30D鏡片3週,測定屈光度、眼軸長,求得配戴前後的差異。屈光度是藉由屈光度計(Infrared photorefractor for mice, 德國圖賓根大學Schaeffel教授製作),眼軸長是藉由SD-OCT (Spectral-domain OCT,譜域光學干涉斷層攝影,Envisu R4310,bioptigen Inc.)來測量。
(待測藥的調製)
使苯基酪酸鈉(Cayman Chemical, MI, USA)及牛磺熊去氧膽酸(Sigma-Aldrich,東京,日本)溶解於PBS。IRE1阻礙劑的STF080310(Selleck Biotech,東京,日本)或4μ8C (Selleck Biotech)、PERK阻礙劑的GSK2656157(Selleck Biotech)或GSK2606414(Selleck Biotech)、ATF6阻礙劑的甲磺酸奈非那韋水合物(東京化學工業,東京,日本)或Ceapin-A7(Sigma-Aldrich)是以DMSO來溶解,以1:1000藉由PBS來稀釋,使用於點眼測試。
(點眼)
將0.2%或2%的苯基酪酸鈉的PBS溶液(4-PBA)、60μM的STF080312(STF)、100μM的4μ8C(4μ8C)、100μM的GSK2656157(GSK)、100μM的GSK2606414(GSK2606414)、100μM的甲磺酸奈非那韋水合物(NFV)、100μM的Ceapin-A7(Ceapin),在近視誘導過程中每天傍晚點眼於兩眼,1天1次,持續10天。
(腹腔內注射)
在近視誘導期間,每天在腹腔內注射(i.p.)苯基酪酸鈉PBS溶液(4-PBA;200mg/kg體重)或牛磺熊去氧膽酸(TUDCA;100mg/kg體重)。
(藉由西方墨點法的濃度測定分析)
鞏膜的蛋白質(10μg/孔)可藉由SDS-PAGE來分離,移至PVDF膜(美國MA州,Merck Millipore),以Blocking One (東京,Nacalai Tesque)來阻斷,與抗ATF6(Bioacademia股份有限公司)、磷酸化-IRE1(Ser724, Abcam, Cambridge, UL)IRE1、磷酸化-eIF2α、eIF2α及β-肌動蛋白(Cell Signaling Technologies Japan,東京,日本)抗體一起在4℃下保溫一晩。將膜與適當的HRP結合二次抗體保溫,使用EzWestLumi plus(ATTA,東京日本)來可視化。SDS-PAGE是使用10%丙烯醯胺凝膠及蛋白分子量標記(MagicMark XP Western Protein Standard, Thermo Fisher Scientific)來進行。使用ImageJ軟體來進行濃度測定分析。
(定量PCR)
定量real time PCR是使用Step One Plus實時PCR系統,Power Up SYBR Green Master Mix(Applied Biosystems, CA, USA)來進行。表現程度是藉由β-肌動蛋白來標準化。
(統計解析)
實驗所得到的數據全部以平均值±標準偏差來表示。群組間差異是藉由Student's t檢定或單因子變異數分析或廣義估計方程式來解析。在顯示ANOVA有顯著差異的情況,接下來進行Tukey HSD,判定各平均值之間差異的顯著性。在p值未達0.05的情況,代表統計學的顯著差異。
[實驗結果]
<測試例1 近視誘導幼齡小鼠鞏膜的內質網壓力反應基因的表現變化>
為了評估內質網壓力反應基因途徑的PERK途徑、ATF6途徑、IRE1途徑與小兒近視進展的關聯,依據上述[實驗方法]的記載來評估模擬小兒近視進展的小鼠的鞏膜的基因表現。
圖2表示了3週近視誘導後的眼軸伸長(a)及屈光度變化(b),將此時鞏膜的基因表現變化表示於圖3。另外,將內質網壓力反應基因的途徑表示於圖4。結果,在近視誘導幼齡小鼠的鞏膜之中,內質網壓力反應主要基因(圖4)的PERK、ATF6、IRE1的下游基因表現明顯亢進(圖3)。
由這些結果確認了,隨著小兒近視進展,PERK途徑、ATF6途徑、IRE1途徑的基因表現會亢進。
<測試例2 由內質網壓力反應基因的各阻礙劑所造成的近視進展抑制>
在測試例1之中,提示了小兒近視進展有PERK、ATF6及IRE1有關聯,因此在此測試例2中,藉由這些基因的已知阻礙劑來評估近視進展的表現型會如何受到影響。此外,PERK阻礙劑使用了GSK2656157(GSK)、GSK2606414,ATF6阻礙劑使用了甲磺酸奈非那韋水合物(NFV)、Ceapin-A7,IRE1阻礙劑使用了STF080312(STF)、4μ8C(圖5)。
圖6-a、b表示在小鼠的近視誘導期間,將60μM的STF、100μM的GSK、100μM的NFV連續10天每天點眼1次之後,眼軸伸長(a)及屈光度變化(b)。圖6-c、d表示將這些阻礙劑的組合(STF+GSK:S+G、GSK+NFV:G+N、NFV+STF:N+S、STF+GSK+NTF:S+G+N)同樣地點眼之後的眼軸伸長(c)及屈光度變化(d)。另外,圖7表示分別將100μM的GSK2606414、Ceapin-A7、4μ8C同樣地點眼之後的眼軸伸長(a)及屈光度變化(b)。
結果,在近視誘導幼齡小鼠的鞏膜之中,藉由內質網壓力反應的主要基因的PERK、ATF6、IRE1的各阻礙劑的單獨點眼,與預測相反地,並未觀察到眼軸伸長抑制及屈光度的近視化的抑制(圖6-a、b)。不如說是,藉由STF以外的阻礙劑的單獨點眼,並未誘導近視的控制組眼睛的眼軸,與DMSO點眼相比顯著伸長,屈光度會近視化。另外,若將這些阻礙劑組合點眼,則僅在至少PERK阻礙劑與ATF6阻礙劑這兩種存在時(G+N、S+G+N),眼軸長明顯受到抑制,屈光度的近視化會受到抑制,也並未觀察到在單獨點眼時觀察到的控制組眼睛的眼軸伸長(圖6-c、d)。此外,與圖6不同的阻礙劑GSK2606414、Ceapin-A7、4μ8C單獨點眼所造成的眼軸長及屈光度的變化,與圖6的結果完全同樣,眼軸伸長及屈光度近視化皆並未受到抑制,在4μ8C以外的單獨點眼的情況,就連控制組眼睛的眼軸也都伸長(圖7)。
由這些結果確認了,內質網壓力途徑的主要基因(PERK、ATF6、IRE1)之中,在至少抑制PERK與ATF6兩者的情況,眼軸伸長會受到抑制,屈光度的近視化會受到抑制。在PERK單獨、ATF6單獨、PERK與IRE1、ATF6與IRE1的抑制的情況,觀察到超過了隨著成長發生的眼軸伸長而導致了疾病性的眼軸伸長。認為這代表抑制PERK途徑與ATF6途徑對於抑制近視而言是重要的。另外,從探索小兒近視進展抑制劑的觀點看來,認為探索可抑制PERK途徑與ATF6途徑兩者的成分是有效的,然而並不受限定。
<測試例3 4-PBA及TUDCA造成的內質網壓力途徑的阻礙>
在測試例2之中,為了探索小兒近視進展抑制劑,認為探索抑制PERK途徑與ATF6途徑兩者的成分是有效的,因此在此測試例3之中,針對已知會抑制眼軸伸長的成分(苯基酪酸鈉{4-PBA}、牛磺熊去氧膽酸{TUDCA}),評估內質網壓力途徑的抑制表現。
圖8表示在小鼠的近視誘導期間,每天在腹腔內注射4-PBA之後的基因表現變化。圖9表示利用4-PBA的投予來進行近視誘導,在第1週、第3週的眼軸伸長(a)與屈光度變化(b)。另外,圖10表示將0.2%與2%4-PBA在近視誘導過程中對小鼠點眼之後的眼軸伸長(a)與屈光變化(b)。另外,圖11表示在近視誘導期間,每天在腹腔內注射TUDCA之後的眼軸伸長(b)與屈光度變化(a)。
結果,在近視誘導幼齡小鼠身上,亢進後的PERK途徑與ATF6途徑下游(圖4)的基因表現,會因為2%4-PBA點眼而明顯受到抑制(圖8)。另外,2%4-PBA點眼第1週與第3週的眼軸伸長,同程度地明顯受到抑制,屈光度的近視化也同程度明顯受到抑制。另外,與此同時,並未誘導近視的控制組眼睛的眼軸伸長(生理性的眼軸伸長)並沒有連帶受到抑制,而僅抑制了近視誘導眼睛的疾病性的眼軸伸長(圖9)。此外,比較0.2%與2%4-PBA的眼軸伸長與屈光度變化的結果,觀察到用量依存的有效性(圖10)。另外,同樣地,即使投予已知作為內質網壓力抑制劑的TUDCA,也與4-PBA同樣地,並未抑制生理性的眼軸伸長,僅抑制了疾病性的眼軸伸長(圖11)。
由這些結果,確認了4-PBA或TUDCA在內質網壓力途徑之中,藉由抑制小兒近視進展抑制機制的PERK途徑與ATF6途徑(圖12),並未抑制隨著正常眼睛成長的生理性的眼軸伸長,僅抑制疾病性的眼軸伸長。亦即確認了,如4-PBA、TUDCA、PERK阻礙劑與ATF6阻礙劑的組合般,抑制PERK與ATF6兩者的成分,不會阻礙小兒從遠視到正視的正常屈光度變化,僅會抑制超過正常的近視進展。
由測試例1~3的結果,藉由利用近視誘導幼齡小鼠模擬人類小兒正視化後接著發生近視進展來進行評估,判明了其疾病性的眼軸伸長的機制(起因於內質網壓力的PERK途徑與ATF6途徑的亢進),據此發現了小兒近視進展抑制劑的探索方法。然後確認了,4-PBA及TUDCA不單是具有眼軸伸長抑制效果,藉由抑制PERK途徑與ATF6途徑,還有不抑制生理性的眼軸伸長,僅抑制疾病性的眼軸伸長的效果。亦即,在in vivo確認了PERK途徑及ATF6途徑的同時阻礙劑可適當地預防、治療小兒近視進展。
<測試例4 在抑制小兒近視進展之中ATF6途徑的關聯性>
在抑制小兒近視進展之中,進一步檢討了PERK途徑與ATF6途徑兩個途徑當中,ATF6途徑關聯到哪個程度。根據上述[實驗方法]的記載,以西方墨點法進行濃度測定分析,求得ATF6的活化form(ATF6-N)量及ATF6的precosor form(ATF6-P)量。近視誘導幼齡小鼠的鞏膜的PERK、ATF6、IRE1各阻礙劑的單獨點眼方法,或阻礙劑組合的點眼方法等,是依據測試例2的記載。
以ATF6的活化form(ATF6-N)量除以ATF6的precosor form(ATF6-P)量之值為活化的指標,表示於圖13。
如圖13所示般,ATF6的ATF6-N的量除以ATF6的ATF6-P的量之值,在幾組中呈現顯著高的值。尤其,在將兩種阻礙劑組合的情況,活性型ATF6呈現高值的組,與分別在圖6c及圖6d所示的觀察到疾病性的眼軸伸長及屈光度降低的組一致。亦即,在近視誘導眼(LIM眼)之中,在ATF6去活化的情況,結果顯示近視化會受到抑制。此相關關係可藉由比較圖6c-d與圖13來明白,若加以統整則如下表1所述。表1中的「STF」或「S」表示IRE1阻礙劑,「GSK」或「G」表示PERK阻礙劑,「NFV」或「N」表示ATF6阻礙劑,與目前為止的測試例同樣。表1統整的結果顯示,在近視眼的鞏膜之中,ATF6途徑的活化會成為觸發因子,隨著眼軸伸長,引起屈光度降低,與其相反地,藉由ATF6途徑的去活化,隨著眼軸伸長,屈光度降低會受到抑制。對於治療、預防小兒近視進展而言,具有此藥效・藥理的藥劑(4-PBA)是有效的。
<測試例5 點眼劑投予對近視誘導造成的水晶體肥厚的影響>
藉由近視誘導(LIM),觀察到水晶體有稍微變厚的傾向。檢討4-PBA的投予形態不同是否對水晶體的變化有影響。根據上述[實驗方法]的記載,對於近視誘導幼齡小鼠點眼或腹腔內投予4-PBA,與眼軸長的測量同樣地,使用SD-OCT測量水晶體的厚度。
如圖14(A)所示般,與DMSO點眼NL(=no lens)組比較,在-30D鏡片配戴組,觀察到水晶體因為近視誘導(LIM)而變厚。在腹腔內投予4-PBA的情況,並未對水晶體的肥厚造成影響。另一方面,如圖14(B)所示般,在藉由點眼投予4-PBA的情況,在-30D鏡片配戴組並未觀察到水晶體的肥厚。亦即代表,從到達目標組織的容易性的觀點看來,4-PBA的投予方法以點眼為適合。
[圖1]為幼齡小鼠的近視誘導的說明圖。(a)為近視誘導模式的構造圖,(b)為近視誘導幼齡小鼠的照片。
[圖2]為表示近視誘導在鞏膜誘發眼軸伸長與內質網壓力之圖形。(a)為小鼠(n=4)近視誘導3週眼軸長的變化(*p<0.05),(b)為小鼠(n=4)近視誘導3週屈光度的變化(*p<0.05)。
[圖3]為小鼠(各組n=8)控制組眼睛(白色長條)及近視誘導眼睛(灰色管柱)的鞏膜在近視誘導第1週及第3週藉由定量PCR測得的內質網壓力反應基因表現程度(*p<0.05)。
[圖4]為表示內質網壓力反應基因的PERK途徑、ATF6途徑、IRE1途徑的說明圖。
[圖5]為表示內質網壓力反應基因的PERK途徑、ATF6途徑、IRE1途徑的各阻礙劑的說明圖。
[圖6]為表示對小鼠點眼PERK途徑、ATF6途徑、IRE1途徑的各阻礙劑所造成的眼軸伸長及屈光度的變化(近視化)之圖形。(a)表示STF080310(STF)、GSK2656157(GSK)及奈非那韋(NFV)的單獨點眼對眼軸伸長造成的影響之圖形(各組n=5)、與DMSO點眼NL(=no lens)組比較的結果(*p<0.05),以及與STF點眼NL組或-30D鏡片配戴組比較的結果(#p<0.05)。(b)表示STF、GSK及NFV的單獨點眼對屈光度的近視化造成的影響的結果(各組n=5)、與DMSO點眼NL組比較的結果(*p<0.05),以及與STF點眼NL組或-30D鏡片配戴組比較的結果(#p<0.05)。(c)表示STF、GSK及NFV的併用點眼對眼軸伸長造成的影響之結果(各組n=4)、與DMSO點眼NL組比較的結果(*p<0.05)。(d)表示STF、GSK及NFV的併用點眼對屈光度的近視化造成的影響之結果(各組n=4)、與DMSO點眼NL組比較的結果(*p<0.05)。
[圖7]為表示與圖6不同的阻礙劑之PERK途徑、ATF6途徑、IRE1途徑的各阻礙劑對小鼠點眼造成的眼軸伸長及屈光度的變化(近視化)之圖形。(a)表示4μ8C、GSK2606414及Ceapin-A7的單獨點眼對眼軸伸長造成的影響之圖形(各組n=5)、與DMSO點眼NL(=no lens)組比較的結果(*p<0.05),以及與4μ8C點眼NL組或-30D鏡片配戴組比較的結果(#p<0.05)。(b)表示4μ8C、GSK2606414及Ceapin-A7的單獨點眼對屈光度的近視化造成的影響之結果(各組n=5)、與DMSO點眼NL組比較的結果(*p<0.05),以及與4μ8C點眼NL組或-30D鏡片配戴組比較的結果(#p<0.05)。
[圖8]為小鼠的近視誘導而誘導出鞏膜內質網壓力之圖形,表示PBS的腹腔內注射(PBS)及苯基酪酸鈉的投予(4-PBA;200mg/kg/天)的鞏膜(各組n=6)之中,藉由定量PCR來測定內質網壓力反應基因的表現,相對於控制組眼睛(白色長條),在近視誘導眼睛(灰色長條)之中基因表現亢進,由4-PBA造成其抑制的結果(*p<0.05)。
[圖9]為小鼠的近視誘導而誘導出眼軸伸長及屈光度的近視化之圖形。(a)表示眼軸伸長在近視誘導(LIM)第1週及第3週因為苯基酪酸腹腔內注射(4-PBA;200mg/kg/天)而受到抑制的結果(各組n=6、*p<0.05),(b)表示屈光度的近視化在近視誘導(LIM)第1週及第3週因為4-PBA投予而受到抑制的結果(各組n=6、*p<0.05)。
[圖10]為小鼠的近視誘導而誘導出眼軸伸長及屈光度的近視化之圖形。(a)表示4-PBA點眼用量依存地抑制眼軸伸長之圖形(各組n=4、*p<0.05),(b)表示4-PBA點眼用量依存地抑制屈光度的近視化之圖形(各組n=4、*p<0.05)。
[圖11]為小鼠的近視誘導而誘導出眼軸伸長及屈光度的近視化之圖形。(a)表示屈光度的近視化因為牛磺熊去氧膽酸的腹腔內注射(TUDCA;100mg/kg體重)而受到抑制之圖形(各組n=4、*p<0.05),(b)表示眼軸伸長因為TUDCA而受到抑制之圖形(各組n=4、*p<0.05)。
[圖12]為表示4-PBA及TUDCA對內質網壓力反應基因的PERK途徑、ATF6途徑、IRE1途徑的抑制機制的說明圖。
[圖13]為測試例4中,評估抑制小兒近視進展之中ATF6途徑的關聯性之圖形。
[圖14]為表示測試例5中,投予形態的不同對於近視誘導所導致的水晶體肥厚造成的影響之圖形。
Claims (7)
- 一種抑制小兒近視進展用點眼劑,其係含有PERK(PKRK-like endoplasmic reticulum kinase)途徑及/或ATF6(Activating transcription factor 6)途徑的阻礙劑作為有效成分。
- 如請求項1之點眼劑,其中前述阻礙劑係選自由苯基酪酸及其藥理學所容許的鹽所成的群組中的至少一種。
- 如請求項1或2之點眼劑,其中前述阻礙劑為苯基酪酸鈉。
- 如請求項1~3中任一項之點眼劑,其中前述阻礙劑的含量,相對於點眼劑總量為0.01~5質量%。
- 如請求項1~4中任一項之點眼劑,其中前述抑制小兒近視進展不會抑制生理性的眼軸伸長。
- 如請求項1~5中任一項之點眼劑,其中前述抑制小兒近視進展會抑制疾病性的眼軸伸長。
- 一種小兒近視進展抑制劑之篩選方法,其係包含:使來自眼睛的細胞接觸候選物質的步驟;及以前述細胞中的PERK及/或ATF6之訊息傳遞鏈的蛋白質及/或基因的變化為指標來選擇候選物質的步驟。
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