CN116761595A - 抑制儿童近视进展用滴眼剂及儿童近视进展抑制剂的筛选方法 - Google Patents
抑制儿童近视进展用滴眼剂及儿童近视进展抑制剂的筛选方法 Download PDFInfo
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Abstract
本发明课题为提供探索抑制PERK通路及/或ATF6通路的成分的筛选方法、及包含有效成分的滴眼剂及组合物,前述有效成分是通过利用该筛选方法而得到的在不阻碍儿童的正常的眼球成长(正视化)的情况下抑制近视进展的有效成分。本发明的解决手段是通过含有PERK(PKRK‑样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分的抑制儿童近视进展用滴眼剂来解决上述课题。通过儿童近视进展抑制剂的筛选方法来解决上述课题,该筛选方法包括:使候选物质接触源自眼的细胞的工序;和以前述细胞中的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化为指标来选择候选物质的工序。
Description
技术领域
本发明涉及为了抑制儿童近视进展所使用的滴眼剂及儿童近视进展抑制剂的筛选方法。进一步详细而言,本发明涉及通过抑制作为儿童近视进展的原因基因的ATF6及/或PERK从而能够在不抑制儿童的正常的眼球成长(将“儿童的正常的眼球成长”称为“正视化”)所需的生理性眼轴伸长的情况下仅抑制造成近视的病理性眼轴伸长的有效成分、及包含该有效成分的滴眼剂以及该有效成分的筛选方法。
根据近视及重度近视相关的最新研究,预测全球近视人口会显著增加,预测到2050年,近视将达到约50亿人,重度近视达到约10亿人(参见非专利文献1)。
另外,依据2019年日本庆应义塾大学医学部的流行病学调查,明确了东京都内小学生689人的近视罹患率为76.5%,尤其在小学1年级时,近视罹患率已经超过60%。另外,同样在东京都内中学生727人的近视罹患率为94.9%,得到无论哪个学年都超过90%的结果(参见非专利文献2)。这已高于东亚其他国家所报道的罹患率,儿童近视在日本可说是达到极严重的程度。
人的眼在刚诞生时为远视,在成长期(到8岁),因为前后方向的眼轴伸长而使光轴伸长,远视的程度会变小,进入学龄期时,则会成为适宜的眼轴长度而正视化。将其称为“生理性眼轴伸长”,该生理性眼轴伸长若因为某些原因而受到损害,则会因为眼轴伸长不足而造成远视,使儿童的生活质量(Quality of Life)显著恶化。另一方面,将正视化后眼轴伸长还没有停止、8岁以后眼轴长度过度伸长称为“病理性眼轴伸长”,这是儿童近视进展的原因,所以,近视会在8岁以后的学龄期急剧进展,一旦伸长的眼轴长度是无法复原的(参见非专利文献3)。
为了抑制儿童近视进展,必须抑制该过度的眼轴伸长(病理性眼轴伸长),然而若连生理性眼轴伸长也抑制,则虽然不会变成近视但是会造成远视,本末倒置。所以,在正确的抑制儿童近视进展策略之中,必须使在抑制病理性眼轴伸长的同时不抑制生理性眼轴伸长这样相反的作用同时成立。
背景技术
现有技术文献
专利文献
专利文献1:国际公开WO2018/164113
非专利文献
非专利文献1:Brien A Holden,等人,“Global prevalence of myopia and highmyopia ando temporal trends from 2000through 2050”,Ophthalmology,Vol.123,Number 5,P.1036-1042(May 2016).
非专利文献2:“中小学生近视增加倾向的警钟(小中学生の近視増加傾向への警鐘)”、日本庆应义塾大学医学部、2019年8月19日新闻稿(https://oklens.co.jp/new/2019/08/21/).
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发明内容
发明所要解决的课题
近年来,与导致儿童近视进展(病理性眼轴伸长)有关的因子已明确。本申请的发明人对该因子组进行认真研究,结果发现,对作为内质网中异常蛋白质的未折叠蛋白进行应答的基因(内质网应激应答基因)与病理性眼轴伸长密切相关(参见专利文献1)。该基因组已知有PERK(PKR-样内质网激酶)、ATF6(转录激活因子6)、IRE1(Inositol requiring 1)这三种,但是应该抑制哪一种基因通路、或者是否抑制全部的通路即可等等、各通路详细的贡献率尚不清楚。如果这些基因通路的抑制不足,则无法期待病理性眼轴伸长的充分抑制,或者如果过度抑制,则可能会抑制生理性眼轴伸长,因此认为同时发生病理性眼轴伸长与生理性眼轴伸长的儿童近视进展的抑制是极为困难的。
用于解决课题的手段
本申请的发明人对内质网应激应答基因(PERK、ATF6、IRE1)的信号转导系统(通路)与病理性眼轴伸长的关联度、各通路的抑制对于抑制眼轴伸长的贡献率、或组合抑制的情况下的协同效果进行了研究。其结果发现,通过抑制PERK通路及/或ATF6通路,病理性眼轴伸长抑制效果提高。另外还发现,选择性地抑制至少ATF6通路,对于抑制儿童近视进展而言是重要的,通过抑制PERK通路及ATF6通路这两通路,充分抑制儿童的病理性眼轴伸长(近视进展)、且同时不抑制生理性眼轴伸长(正视化)。
本发明的目的在于提供探索抑制PERK通路及/或ATF6通路的成分的筛选方法。另外还通过该筛选方法得到在不阻碍儿童的正常的眼球成长(正视化)的情况下抑制近视进展的有效成分,提供包含该有效成分的滴眼剂。此外还提供一种方法,针对被认为对近视有效的各种成分,检验该成分对同时进行着病理性眼轴伸长与生理性眼轴伸长的儿童而言是否安全,即检验是否因伸长不足造成远视或者因过度伸长造成近视。
即,本发明为:
[1]抑制儿童近视进展用滴眼剂,其含有PERK(PKR-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分。
[2]如上述[1]所述的滴眼剂,其中,前述抑制剂为选自由苯基丁酸及其药理学上容许的盐组成的组中的至少一种。
[3]如上述[1]或[2]所述的滴眼剂,其中,前述抑制剂为苯基丁酸钠。
[4]如上述[1]~[3]中任一项所述的滴眼剂,其中,前述抑制剂的含量相对于滴眼剂总量而言为0.01~5质量%。
[5]如上述[1]~[4]中任一项所述的滴眼剂,其中,前述抑制儿童近视进展不会抑制生理性眼轴伸长。
[6]如上述[1]~[5]中任一项所述的滴眼剂,其中,前述抑制儿童近视进展对病理性眼轴伸长进行抑制。
[7]儿童近视进展抑制剂的筛选方法,其包括:使候选物质接触源自眼的细胞的工序;和以前述细胞中的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化为指标来选择候选物质的工序。
发明效果
根据本发明,可提供探索抑制PERK及/或ATF6的信号转导系统的成分的筛选方法。通过这样的筛选方法,可提供在不阻碍儿童的生理性眼轴伸长(正视化)的情况下抑制近视进展的有效成分,并可提供包含该有效成分的滴眼剂及组合物。
附图说明
[图1]为幼龄小鼠的近视诱导的说明图。(a)为近视诱导的示意性结构图,(b)为近视诱导幼龄小鼠的照片。
[图2]为示出近视诱导在巩膜中诱发眼轴伸长与内质网应激的图表。(a)为小鼠(n=4)的近视诱导3周的眼轴长度的变化(*p<0.05),(b)为小鼠(n=4)的近视诱导3周的屈光的变化(*p<0.05)。
[图3]为小鼠(各组n=8)的对照眼(白色柱)及近视诱导眼(灰色柱)的巩膜在近视诱导第1周及第3周通过定量PCR测得的内质网应激应答基因表达水平(*p<0.05)。
[图4]为示出作为内质网应激应答基因的PERK通路、ATF6通路、IRE1通路的说明图。
[图5]为示出作为内质网应激应答基因的PERK通路、ATF6通路、IRE1通路各自的各种抑制剂的说明图。
[图6]为示出对小鼠滴眼PERK通路、ATF6通路、IRE1通路的各种抑制剂所引起的眼轴伸长及屈光的变化(近视化)的图表。(a)为示出STF080310(STF)、GSK2656157(GSK)及奈非那韦(NFV)的单独滴眼对眼轴伸长造成的影响的图表(各组n=5),是与DMSO滴眼NL(=nolens,无透镜)组比较的结果(*p<0.05)及与STF滴眼NL组或-30D透镜佩戴组比较的结果(#p<0.05)。(b)为示出STF、GSK及NFV的单独滴眼对屈光的近视化造成的影响的结果(各组n=5),是与DMSO滴眼NL组比较的结果(*p<0.05)及与STF滴眼NL组或-30D透镜佩戴组比较的结果(#p<0.05)。(c)为示出STF、GSK及NFV的并用滴眼对眼轴伸长造成的影响的结果(各组n=4),是与DMSO滴眼NL组比较的结果(*p<0.05)。(d)为示出STF、GSK及NFV的并用滴眼对屈光的近视化造成的影响的结果(各组n=4),是与DMSO滴眼NL组比较的结果(*p<0.05)。
[图7]为示出与图6不同的抑制剂中的PERK通路、ATF6通路、IRE1通路的各种抑制剂对小鼠滴眼造成的眼轴伸长及屈光的变化(近视化)的图表。(a)为示出4μ8C、GSK2606414及Ceapin-A7的单独滴眼对眼轴伸长造成的影响的图表(各组n=5),是与DMSO滴眼NL(=无透镜)组比较的结果(*p<0.05)及与4μ8C滴眼NL组或-30D透镜佩戴组比较的结果(#p<0.05)。(b)为示出4μ8C、GSK2606414及Ceapin-A7的单独滴眼对屈光的近视化造成的影响的结果(各组n=5),是与DMSO滴眼NL组比较的结果(*p<0.05)及与4μ8C滴眼NL组或-30D透镜佩戴组比较的结果(#p<0.05)。
[图8]为小鼠的近视诱导诱导出巩膜内质网应激的图表,通过定量PCR来测定在PBS的腹腔注射(PBS)及苯基丁酸钠的施予(4-PBA;200mg/kg/天)的巩膜(各组n=6)中内质网应激应答基因的表达,相对于对照眼(白色柱),在近视诱导眼(灰色柱)中基因表达亢进,表示由4-PBA造成其抑制的结果(*p<0.05)。
[图9]为小鼠的近视诱导诱导出眼轴伸长及屈光的近视化的图表。(a)为示出眼轴伸长在近视诱导(LIM)第1周及第3周的因苯基丁酸的腹腔注射(4-PBA;200mg/kg/天)而受到抑制的结果(各组n=6、*p<0.05),(b)为示出屈光的近视化在近视诱导(LIM)第1周及第3周的因4-PBA施予而受到抑制的结果(各组n=6、*p<0.05)。
[图10]为小鼠的近视诱导诱导出眼轴伸长及屈光的近视化的图表。(a)为示出4-PBA滴眼用量依赖性地抑制眼轴伸长的图表(各组n=4、*p<0.05),(b)为示出4-PBA滴眼用量依赖性地抑制屈光的近视化的图表(各组n=4、*p<0.05)。
[图11]为小鼠的近视诱导诱导出眼轴伸长及屈光的近视化的图表。(a)为示出屈光的近视化因牛磺熊去氧胆酸的腹腔注射(TUDCA;100mg/kg体重)而受到抑制的图表(各组n=4、*p<0.05),(b)为示出眼轴伸长因TUDCA而受到抑制的图表(各组n=4、*p<0.05)。
[图12]为示出4-PBA及TUDCA对作为内质网应激应答基因的PERK通路、ATF6通路、IRE1通路的抑制机制的说明图。
[图13]为试验例4中对抑制儿童近视进展中的ATF6通路的参与进行评价的图表。
[图14]为示出试验例5中施予形态的不同对近视诱导所导致的晶状体肥厚造成的影响的图表。
具体实施方式
以下详细说明本发明。本发明并不受以下的实施方式及实验例限定,在包含本发明要旨的范围内包含各种变形例、应用例。
[抑制儿童近视进展用滴眼剂]
本发明所涉及的抑制儿童近视进展用滴眼剂含有PERK(PKR-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分。
在本说明书中,PERK通路及/或ATF6通路的抑制剂是指,对PERK的信号转导系统(PERK通路)及/或ATF6的信号转导系统(ATF6通路)具有抑制效果的物质。对这些信号转导系统的抑制效果可如后述实施例那样通过已知的方法以参与这些信号转导系统的基因及/或蛋白质的变化为指标来进行评价。
(PERK通路及/或ATF6通路的抑制剂)
如上所述,作为与儿童近视进展(病理性眼轴伸长)有关的因子,对作为内质网中的异常蛋白质的未折叠蛋白进行应答的基因通路参与病理性眼轴伸长。该基因通路已知有PERK通路、ATF6通路及IRE1通路这三种,如后述实验例所示,新发现了至少抑制ATF6通路对于抑制近视而言是必须的。另外还新发现了在这三种通路之中,通过抑制PERK通路与ATF6通路,抑制儿童近视进展效果进一步提高。还确认到仅抑制PERK通路或ATF6通路中的任一者时,有时会代偿性地激活另一个通路。因此,虽不予限定,在一个实施方式中,对于PERK通路与ATF6通路中的任一者均具有抑制效果的物质可成为抑制儿童近视进展的有效成分。
即,能以与PERK及/或ATF6的信号转导有关的基因或蛋白质为靶标,将可使它们减少的化合物、可降低PERK通路及/或ATF6通路的蛋白质表达的反义寡核苷酸、siRNA等核酸作为对抑制儿童近视进展有效的成分而配合于滴眼剂。
在本说明书中,PERK通路或ATF6通路的抑制剂是指,对内质网中的PERK的信号转导系统或ATF6的信号转导系统具有抑制效果的物质。对这些信号转导系统的抑制效果可通过后述实验例所记载的方法、或通过已知的方法,以参与这些信号转导系统的基因及/或蛋白质的变化作为指标来进行评价。
在对与PERK的信号转导系统有关的因子的基因表达或蛋白质表达进行评价时,可通过与不添加候选物质的对照相比较,该因子的表达因为候选物质至少变动1%来进行评价。
另外,在评价与ATF6的信号转导系统相关的因子的基因表达或蛋白质表达时,可通过与不添加候选物质的对照相比较,由候选物质使该因子的表达变动至少1%来进行评价。
PERK是内质网跨膜型激酶,作为与其信号转导有关的因子,可举出例如eIF2α(真核起始因子2α)、ATF4(转录激活因子4)、CHOP(C/EBP同源蛋白)、GADD34(生长停滞DNA与损伤诱导蛋白34,growth arrest DNA and damage protein 34)等。
另外,ATF6是属于CREB/ATF家族的膜结合型转录因子,作为与其信号转导有关的因子,可举出例如BiP(结合免疫球蛋白,Binding immunoglobulin protein,也称为“GRP78”)、Txndc12(thioredoxin domain containing 12,也称为“ERp18”)、S1P(位点1蛋白酶,site-1protease)、S2P(位点2蛋白酶,site-2protease)等。
在后述实验例中,通过筛选可抑制PERK通路与ATF6通路这两者的成分,发现了选自由苯基丁酸、牛磺熊去氧胆酸及其药理学上容许的盐组成的组中的至少一种。然而,并不限于此,也可使用新鉴定为至少抑制ATF6通路的成分的成分、或新鉴定为抑制PERK通路与ATF6通路的成分的成分。作为ATF6通路的抑制剂,并不受限定,从在滴眼剂中的溶解性的观点考虑,优选为苯基丁酸钠。如后述实验例所记载,如果是苯基丁酸钠,则在ATF6通路之外,还可抑制PERK通路,故而优选。PERK通路及/或ATF6通路的抑制剂可通过已知的方法进行合成而使用,也可购买市售品而使用。
在本说明书中,“药学上容许的盐”并没有特别限制,具体而言,可举出有机酸盐、无机酸盐、有机碱或无机碱。作为有机酸盐,可举出例如乙酸盐、三氟乙酸盐、丁酸盐、棕榈酸盐、硬脂酸盐等单羧酸盐;富马酸盐、马来酸盐、琥珀酸盐、丙二酸盐等多元羧酸盐;乳酸盐、酒石酸盐、柠檬酸盐等羟基羧酸盐;甲烷磺酸盐、甲苯磺酸盐、对甲苯磺酸盐等有机磺酸盐。作为无机酸盐,可举出例如盐酸盐、硫酸盐、硝酸盐、氢溴酸盐、磷酸盐。作为与有机碱的盐,可举出例如与甲基胺、三乙基胺、三乙醇胺、二乙醇胺、吗啉、哌嗪、吡咯烷、三吡啶、甲基吡啶、乙二胺等有机胺的盐。作为与无机碱的盐,可举出例如铵盐;与钠或钾等碱金属、钙或镁等碱土金属、铝等金属的盐等各种盐。这些盐可单独使用一种,也可任意组合使用两种以上。“药学上容许的盐”也可包括盐的溶剂合物或水合物。
PERK通路及/或ATF6通路的抑制剂的含量可根据用法、用量、添加剂的种类等适当地变更。例如相对于滴眼剂总量(总质量,在本说明书中均相同),优选为0.01质量%以上,更优选为0.05质量%以上,进一步优选为0.1质量%以上,特别优选为0.2质量%以上。另外,PERK通路及/或ATF6通路的抑制剂的含量,例如相对于滴眼剂总量,优选为5质量%以下,更优选为4质量%以下,进一步优选为3质量%以下,特别优选为2质量%以下。另外,PERK通路及/或ATF6通路的抑制剂的含量,例如相对于滴眼剂总量,优选为0.01~5质量%,更优选为0.05~4质量%,进一步优选为0.1~3质量%,特别优选为0.2~2质量%。
在使用选自由苯基丁酸及其药理学上容许的盐组成的组中的至少一种作为PERK通路及/或ATF6通路的抑制剂的情况下,其含量例如相对于滴眼剂总量而言优选为0.01~5质量%,更优选为0.05~4质量%,进一步优选为0.1~3质量%,特别优选为0.2~2质量%。
[用途]
本发明所涉及的滴眼剂可用于抑制儿童近视进展用途。在本说明书中,儿童是指7岁以上未满15岁的儿童。眼的屈光的程度,在出生后为轻度的远视,到学龄期眼轴会伸长直至大致为正视。
眼轴长度在出生后至2岁左右急速伸长,其后便缓慢伸长。这种与成长相伴的直至正视化的眼轴伸长称为“生理性眼轴伸长”,是眼的正常成长所不可或缺的现象。然而在学龄期以后眼轴长度也继续伸长则会导致近视进展,因此被认为是“病理性眼轴伸长”。例如就病理性眼轴伸长而言,成人的眼中眼轴长度伸长1mm会导致增加约3.0D的近视度数,而且眼轴伸长不会复原。
因此,在抑制儿童近视进展时,需要不抑制生理性眼轴伸长(正视化),而抑制病理性眼轴伸长(近视进展)。在后述实验例中,新发现了至少抑制ATF6通路对于抑制近视而言是必须的。在仅抑制PERK通路或ATF6通路中的任一者的情况下,也确认到会有代偿性地激活另一个通路的情况。因此,虽不予限定,在一个实施方式中,发现了通过抑制PERK通路与ATF6通路这两者,病理性眼轴伸长抑制效果协同地提高。根据这样的机制,能够在不抑制生理性眼轴伸长(正视化)的情况下下抑制儿童近视进展。
(剂型)
本发明所涉及的组合物可作为滴眼剂来使用。在本发明中,抑制儿童近视进展用滴眼剂的剂型并没有限定,可举出例如水性滴眼剂、用时溶解滴眼剂、悬浮性滴眼剂、油性滴眼剂、眼软膏剂等。上述之中,从显著发挥本发明的效果的观点考虑,优选为水性滴眼剂。
在滴眼剂中,除了上述成分之外,可配合其他有效成分(药理活性成分、生理活性成分等)。这样的成分的种类没有特别限制,可举出例如减充血成分、眼肌调节药成分、抗发炎药成分、收敛药成分、抗组胺药成分、抗过敏药成分、维生素类、氨基酸类、抗菌药成分、糖类、高分子化合物或其衍生物、纤维素或其衍生物、局部麻醉药成分等。
在滴眼剂中,在不损害本发明效果的范围内,可进一步根据其用途或形态按照常用方法适当地选择各种成分或添加物,使其含有一种或并用含有两种以上。作为这些成分或添加物,可举出例如液体制剂等的制备中通常使用的载体、香料或清凉剂、防腐剂、杀菌剂或抗菌剂、pH调节剂、螯合剂、稳定剂、等渗剂、缓冲剂、增稠剂等各种添加剂。以下例示出滴眼剂中使用的代表性成分,但不限于此。
作为载体,可举出例如水、含水乙醇等水性溶剂。需要说明的是,当各种成分难溶于水性溶剂时,也可使用增溶剂。作为增溶剂,可举出例如聚氧乙烯氢化蓖麻油、聚氧乙烯40硬脂酸酯、聚维酮、聚山梨酯80等。
作为香料或清凉剂,可举出例如萜烯类(具体而言,茴香脑、丁香酚、樟脑、香叶醇、桉叶油醇、冰片、薄荷醇、柠檬烯、龙脑等,它们可为d体、l体或dl体中的任意)、精油(茴香油、清凉薄荷油、肉桂油、留兰香油、薄荷水、薄荷油、胡椒薄荷油(peppermint oil)、佛手柑油、尤加利油、玫瑰油等)等。
作为防腐剂、杀菌剂或抗菌剂,可举出例如泊利氯铵、盐酸烷基二氨基乙基甘氨酸、苯甲酸钠、乙醇、苯扎氯铵、苄索氯铵、葡萄糖酸氯己啶、氯丁醇、山梨酸、山梨酸钾、脱水乙酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、硫酸羟基喹啉、苯乙醇、苄醇、双胍化合物(具体而言,聚六亚甲基双胍或其盐酸盐等)、Glokill(Rhodia公司制的商品名)等。
作为pH调节剂,可举出例如盐酸、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、三乙醇胺、单乙醇胺、二异丙醇胺、硫酸、磷酸等。
作为螯合剂,可举出例如抗坏血酸、依地酸四钠、依地酸钠、柠檬酸等。
作为稳定剂,可举出例如依地酸钠水合物、聚维酮、聚山梨酯80、二丁基羟基甲苯、氨丁三醇、甲醛次硫酸氢钠(吊白块)、生育酚、焦亚硫酸钠、单乙醇胺、单硬脂酸铝、单硬脂酸甘油酯等。
作为等渗剂,可举出例如氯化钾、氯化钠、浓甘油、葡萄糖、D-甘露醇等。
作为缓冲剂,可举出例如柠檬酸钠水合物、乙酸钠水合物、碳酸氢钠、氨丁三醇、硼酸、硼砂、磷酸氢钠水合物、磷酸二氢钠等。
作为增稠剂,可举出例如羧基乙烯基聚合物、聚维酮、聚乙烯醇(部分皂化物)、羟乙基纤维素、羟丙甲纤维素、甲基纤维素、甘油等。
在本发明所涉及的滴眼剂中,可在期待本发明的效果或不阻碍本发明的效果的范围内配合添加剂。其含量没有特别限定,相对于滴眼剂总量,优选为0.001~1质量%左右。
滴眼剂的pH只要调成3~10即可,从使用感的观点考虑,优选为4~9,从使用感的观点考虑,更优选为5~8.5。
作为收容本发明所涉及的滴眼剂的容器,可没有限制地使用已知的滴眼容器。作为滴眼容器,通常可使用可对眼睛滴下滴眼剂的形状,例如具备滴嘴且于滴嘴前端具备容器口的形状的容器。另外,作为滴眼容器,可以是在容器上安装有与其分开成型的滴嘴的结构的滴眼容器、及滴嘴部(液体的流出部)与容器主体一体成型的结构的滴眼容器(例如一次性的滴眼容器等)中的任一种。
滴眼容器通常只要采用塑料容器即可。关于塑料容器的构成材料,没有特别限制,可举出例如聚对苯二甲酸乙二酯、聚芳酯、聚萘二甲酸乙二酯、聚碳酸酯、聚乙烯、聚丙烯、聚酰亚胺中的任一种,它们的共聚物或它们的两种以上的混合物。尤其是从在适度的挤出等下容易发挥本发明的效果的观点考虑,优选聚对苯二甲酸乙二酯、聚芳酯、聚萘二甲酸乙二酯或它们的共聚物、或它们的两种以上的混合物。
滴眼剂可填充于以这样的材料为主材料的透明容器(具备不妨碍到观察异物的程度的透明性的容器),也可填充于避光容器。避光例如可通过在透明容器材料中添加着色剂来进行,也可通过用收缩薄膜或外盒等包覆容器来避光。另外,为了在适度的挤出等下容易进一步发挥出本发明的效果,容器的容量优选为0.5~50mL左右,更优选为3~20mL左右。
另外,关于滴眼容器所具备的滴嘴,对于其结构或构成材料也没有特别限制。关于滴嘴的结构,只要是作为滴眼容器的滴嘴而一般所采用的结构即可。另外,关于滴嘴的构成材料,可例示例如与上述塑料容器的构成材料同样的材料。从使滴眼剂的断液更良好、且抑制滴入量的不均的观点考虑,包含聚乙烯或聚丙烯作为构成材料的滴嘴是适宜的。作为聚乙烯的种类,可举出高密度聚乙烯、低密度聚乙烯等,其中包含低密度聚乙烯作为构成材料的滴嘴是适宜的。
(滴眼剂的制造方法)
本发明所涉及的滴眼剂可用本领域技术人员惯用或已知的方法来制备。例如通过下述方式制备即可:通过使各成分分散于水等载体后,若有需要则添加增溶剂,根据需要进行加热,使用均质机等使其均匀化、溶解或乳化,并用pH调节剂调节pH。另外,作为制剂的灭菌方法,可选择电子束灭菌、高压釜灭菌、过滤灭菌等方法。
(使用方法)
本发明所涉及的滴眼剂的用法及用量根据患者的症状等而变动,通常只要以1天约1~6次、1次约1~2滴进行滴眼即可。
本发明所涉及的滴眼剂可对儿童适用。虽不予限定,作为PERK通路及/或ATF6通路的抑制剂而使用含有选自由苯基丁酸及其药理学上容许的盐组成的组中的至少一种的滴眼剂时,例如能以1天1~2次、1次1~2滴滴入滴眼剂,优选以1天1次、1次1滴进行滴眼。
另外,从显著发挥本发明的效果的观点考虑,本发明所涉及的滴眼剂可在例如午睡前、就寝前等活动不活跃的时间带对儿童使用。
[儿童近视进展抑制剂的筛选方法]
在本发明中,儿童近视进展抑制剂的筛选方法包括:使候选物质接触源自眼的细胞的工序;和以前述细胞中的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化为指标来选择候选物质的工序。虽不予限定,例如可在存在候选物质的条件下或不存在候选物质的条件下接触细胞,测定候选物质所引起的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化并加以比较来进行候选物质的筛选。
作为源自眼的细胞,虽不予限定,从显著发挥本发明的效果的观点考虑,优选为巩膜中的细胞,更优选为巩膜成纤维细胞。
虽不予限定,源自眼的细胞优选为来源于诱导近视的动物模型的细胞。作为这样的近视诱导模型,可利用已知的动物模型。
虽不予限定,作为近视诱导模型,可举出佩戴负透镜而诱导近视的动物模型、通过施予近视诱导剂为诱导近视的动物模型等。
作为这样的负透镜,可利用-20~-40屈光度(D)的负透镜,优选为-25~-35屈光度(D)的负透镜。负透镜的佩戴方法可使用已知的方法,虽不予限定,可举出使用固定件将负透镜固定于动物的眼前等。
负透镜的佩戴期间可设为例如至少1周,优选2周以上,更优选3周以上。
另外,作为近视诱导剂,可利用已知的物质,例如作为近视诱导剂,如后述实验例中的评价所述,可使用衣霉素、毒胡萝卜素等。另外,作为近视诱导剂,也可组合使用PERK通路的激活剂、ATF6通路的激活剂。作为PERK通路的激活剂,可举出CCT020312等,作为ATF6通路的激活剂,可举出AA147等,可单剂施予或混合施予这些激活剂,优选混合施予这些激活剂。
就这样的近视诱导剂而言,虽不予限定,从作用于巩膜等的眼细胞的观点考虑,例如可制成注射剂或滴眼剂而进行施予,优选制成滴眼剂而进行施予。在使用衣霉素作为滴眼剂时,例如可设为10~100μg/mL,优选为20~80μg/mL,更优选为40~60μg/mL。
在使用毒胡萝卜素作为滴眼剂时,例如可设为1~100μM,优选为2~60μM,更优选为5~30μM。
关于对动物诱导近视的开始时期,从制作出预设应用于儿童的动物模型的观点考虑,优选使用幼龄动物。虽不予限定,为小鼠的情况下,优选在断奶时期开始佩戴负透镜,更优选为3周龄小鼠。就C57BL6等小鼠而言,从3周龄到6周龄会发生生理性眼轴伸长。因此,自3周龄起诱导近视,除了生理性眼轴伸长之外,也可促进过度的眼轴伸长,故而可发生病理性眼轴伸长。例如优选在对3周龄小鼠进行近视诱导前后或进行近视诱导期间施用候选物质。根据该手法,可评价候选物质对生理性眼轴伸长或病理性眼轴伸长造成的影响。另外,作为动物使用白色来亨鸡的情况下,从制作出预设应用于儿童的动物模型的观点考虑,例如优选使用5天龄的白色来亨鸡幼鸡。
虽不予限定,就使候选物质接触源自眼的细胞的步骤而言,优选通过口服、腹腔注射或滴眼而施予该候选物质,更优选通过滴眼而施予。例如对巩膜中的细胞进行评价时,可使滴眼剂中含有候选物质而进行施予。
在测定候选物质所引起的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化的步骤中,可使用已知的评价方法。虽不予限定,基因的表达或蛋白质的表达或分泌可通过微阵列、实时PCR法、PCR法、Western印迹法、ELISA法、免疫组织染色等已知方法来测定。
例如在测定PERK或ATF6的信号转导系统的基因变化时,可使用已知的RNA提取方法从培养细胞中提取出RNA,并供于对mRNA表达进行定量分析的步骤。
就对mRNA的表达进行定量分析的步骤而言,虽不予限定,优选使用实时PCR法。作为用实时PCR法进行测定的标志物,能以在(PERK通路及ATF6通路的抑制剂)的项目所述的与信号转导有关的因子作为测定项目。
作为与PERK通路有关的因子,可举出例如CHOP、ATF4、GADD34等。
作为与ATF6通路有关的因子,可举出例如GRP78、GRP94、PDI、Cnex、HYOU、ERdj3等。
在PERK及/或ATF6的信号转导系统的蛋白质及/或基因的表达因为候选物质而受到抑制的情况下,可选定该候选物质作为PERK通路及/或ATF6通路的抑制剂,能作为儿童近视进展抑制剂来使用。
本发明可以为以下方式。
抑制儿童近视进展用滴眼剂,其含有PERK(PKRK-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分;
含有PERK(PKRK-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分的滴眼剂用于抑制儿童近视进展中的用途;
PERK(PKRK-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂在抑制儿童近视进展用滴眼剂的制造中的用途;
抑制儿童近视进展方法,其包括使人摄取有效量的PERK(PKRK-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂;
如上述所记载的滴眼剂、用途或方法,其包括:前述抑制剂至少选择性地抑制ATF6通路;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂为PERK通路及ATF6通路这两通路的抑制剂;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂为选自由苯基丁酸及其药理学上容许的盐组成的组中的至少一种;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂为苯基丁酸钠;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂的含量相对于滴眼剂总量而言为0.01~5质量%;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂的含量相对于滴眼剂总量而言为0.1~3质量%;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制剂的含量相对于滴眼剂总量而言为0.2~2质量%;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制儿童近视进展不会抑制生理性眼轴伸长;
如上述所记载的滴眼剂、用途或方法,其中,前述抑制儿童近视进展对病理性眼轴伸长进行抑制;
如上述所记载的滴眼剂、用途或方法,其中,前述儿童包括7岁以上未满15岁的儿童;
如上述所记载的滴眼剂、用途或方法,其中,前述滴眼剂为水性滴眼剂;
如上述所记载的滴眼剂、用途或方法,其中,前述滴眼剂以1天1~2次的滴眼而使用;
如上述所记载的滴眼剂、用途或方法,其中,前述滴眼剂以1天1~2次的滴眼而使用;
如上述所记载的滴眼剂、用途或方法,其中,前述滴眼剂在午睡前或就寝前使用;
儿童近视进展抑制剂的筛选方法,其包括:使候选物质接触源自眼的细胞的工序;和以前述细胞中的PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化为指标来选择候选物质的工序;
如上述所记载的筛选方法,其中,前述源自眼的细胞为来源于诱导近视的动物模型的细胞;
如上述所记载的筛选方法,其中,前述动物模型是佩戴负透镜而诱导近视的动物模型、或通过施予近视诱导剂而诱导近视的动物模型;
如上述所记载的筛选方法,其中,前述负透镜为-20~-40屈光度(D)的透镜;
如上述所记载的筛选方法,其中,前述负透镜的佩戴期间为至少1周;
如上述所记载的筛选方法,其中,前述近视诱导剂包含衣霉素及/或毒胡萝卜素;
如上述所记载的筛选方法,其中,前述衣霉素的滴眼施予时的浓度为10~100μg/mL;
如上述所记载的筛选方法,其中,前述毒胡萝卜素的滴眼施予时的浓度为1~100μM;
如上述所记载的筛选方法,其中,前述动物模型在断奶时期开始佩戴负透镜;
如上述所记载的筛选方法,其中,使候选物质接触前述源自眼的细胞的工序包括:通过口服、腹腔注射或滴眼而施予前述候选物质;
如上述所记载的筛选方法,其包括:当PERK及/或ATF6的信号转导系统的蛋白质及/或基因的表达因为候选物质而受到抑制时,选择该候选物质作为儿童近视进展抑制剂;
如上述所记载的筛选方法,其包括:当PERK及ATF6的信号转导系统的蛋白质及/或基因的表达因为候选物质而受到抑制时,选择该候选物质作为儿童近视进展抑制剂。
实施例
以下举出实验结果对本发明作具体说明。
[实验方法]
本实验中的所有动物实验得到日本庆应义塾大学动物实验委员会的批准,遵守庆应义塾大学动物实验相关的设施指南、眼科·视觉研究中的动物使用相关的ARVO声明、动物研究:研究中的动物使用相关的体内(in vivo)实验报告(ARRIVE)指南。
(近视诱导幼龄小鼠的特征)
如非专利文献3所记载,人眼在刚出生时为远视,其后眼轴会伸长(即近视化),在学龄期(8岁时)正视化。另外,如非专利文献6所记载,在小鼠(C57BL6)的3至6周龄的期间,眼轴也会随着成长而伸长。因此,从近视进展动态的观点考虑,该近视诱导幼龄小鼠相当于人类8岁前后,这实质上相当于幼儿、儿童(学龄期)。通过使用该动物模型,可阐明人类儿童近视进展的机制,能够筛选出儿童近视进展治疗剂。
图1(a)示意性地示出佩戴负透镜而诱导轴性近视的机理。正视是指进入眼的平行光线在视网膜上成像,因此可清楚地看到影像的状态。另一方面,轴性近视是指因眼轴长度变长,进入眼的平行光线在视网膜的前方成像而无法看清的状态。包括人类在内,动物的眼会随着成长而变大。若使幼龄的小鼠佩戴负透镜,则眼轴会伸长至佩戴负透镜时成像的位置、即佩戴负透镜时可看清的状态。其结果,眼轴伸长,可形成与轴性近视同样的眼的状态。
(近视诱导幼龄小鼠的制作)
具体而言,如下制作近视诱导幼龄小鼠。需要说明的是,近视诱导、眼轴长度及屈光的测量以与非专利文献4、5同样的方法来进行。首先,在12小时明暗循环下于温度控制洁净室中将雄性C57BL6J小鼠收容于标准透明笼中。使动物自由摄取标准饲料与经高压蒸气灭菌的自来水。将刚断奶的3周龄小鼠用Domitor(日本全药工业株式会社)、Vetorphale(Meiji Seika Pharma株式会社)、咪达唑仑(Sandoz株式会社)这三种混合麻醉药来进行麻醉,用剪刀使头盖骨露出。如图1(b)所示,在头盖骨上设立支柱,以牙科用黏固剂(Super-Bond,Sun Medical株式会社)来固定。支柱以可用螺帽固定后述调节器具的方式设有螺纹牙。
为了诱导近视,在右眼(近视诱导眼)佩戴-30屈光度(diopter,D)的负透镜(RAINBOW CONTACT,RAINBOW OPTICAL研究所株式会社),在左眼(对照眼)佩戴0D的透镜或仅佩戴镜框以作为对照。将透镜佩戴于小鼠时,为了防止小鼠通过前肢等造成损伤,在透镜下部的镜框部粘接朝侧向突出的形状的护具。由于护具,小鼠不会触碰到透镜,不会损伤透镜。就护具而言,在此处使用粘接于镜框部而成为一体的护具,但只要透镜不被小鼠的行为损伤即可,无需与透镜成为一体。例如,也可为如遭受外伤动物所佩戴的伊丽莎白圈那样的形状的护具。
在透镜上方的镜框部,配合小鼠的成长而粘接有用于对佩戴的透镜的幅度或角度进行调节的调节器具。调节器具弯成“ㄑ”字形,一侧粘接有透镜,另一侧则以可佩戴于设立在头部的支柱的方式设有长孔。使长孔通过支柱,以螺帽进行螺旋固定,由此可在不压迫小鼠双眼的周缘的情况下使其密合于皮肤而固定。通过由支柱、螺帽、调节器具这3件形成的调节机构,可配合小鼠的成长调节幅度、角度,调节成透镜对准小鼠眼睛的位置。另外,由于可取下透镜,因此可测量眼轴长度、屈光值的经时变化。
(眼轴伸长与屈光的测量)
对照眼仅佩戴镜框,近视诱导眼则佩戴-30D透镜3周,测定屈光值、眼轴长度,求出佩戴前后的差。屈光值利用屈光计(Infrared photorefractor for mice、Tubingen大学Schaeffel教授制作)来测量,眼轴长度利用SD-OCT(Spectral-domain OCT,Envisu R4310、bioptigen Inc.)来测量。
(受试药的制备)
苯基丁酸钠(Cayman Chemical,MI,USA)及牛磺熊去氧胆酸(Sigma-Aldrich,东京,日本)溶解于PBS。IRE1抑制剂STF080310(Selleck Biotech,东京,日本)或4μ8C(Selleck Biotech)、PERK抑制剂GSK2656157(Selleck Biotech)或GSK2606414(SelleckBiotech)、ATF6抑制剂甲磺酸奈非那韦水合物(东京化学工业,东京,日本)或Ceapin-A7(Sigma-Aldrich)用DMSO溶解,利用PBS以1:1000进行稀释而用于滴眼试验。
(滴眼)
在近视诱导中将0.2%或2%的苯基丁酸钠的PBS溶液(4-PBA)、60μM的STF080312(STF)、100μM的4μ8C(4μ8C)、100μM的GSK2656157(GSK)、100μM的GSK2606414(GSK2606414)、100μM的甲磺酸奈非那韦水合物(NFV)、100μM的Ceapin-A7(Ceapin)在10天期间每天以1天1次在傍晚滴眼于两眼。
(腹腔注射)
在整个近视诱导期间,每天腹腔注射(i.p.)苯基丁酸钠PBS溶液(4-PBA;200mg/kg体重)或牛磺熊去氧胆酸(TUDCA;100mg/kg体重)。
(通过Western印迹法的浓度测定分析)
巩膜的蛋白质(10μg/孔)利用SDS-PAGE进行分离,并转移至PVDF膜(美国MA州,Merck Millipore),用Blocking One(东京,Nacalai Tesque)进行封闭,与抗ATF6(Bioacademia株式会社)、磷酸化-IRE1(Ser724,Abcam,Cambridge,UL)IRE1、磷酸化-eIF2α、eIF2α及β-肌动蛋白(Cell Signaling Technologies Japan,东京,日本)抗体一同于4℃孵育一夜。将膜与适宜的HRP偶联二抗进行孵育,使用EzWestLumi plus(ATTA,东京日本)进行可视化。SDS-PAGE在10%丙烯酰胺凝胶上使用蛋白分子量标记物(MagicMark XPWestern Protein Standard,Thermo Fisher Scientific)来进行。使用ImageJ软件来进行浓度测定分析。
(定量PCR)
定量实时PCR使用Step One Plus实时PCR系统,用Power Up SYBR Green MasterMix(Applied Biosystems,CA,USA)来进行。表达水平利用β-肌动蛋白进行标准化。
(统计分析)
实验所得到的数据均以平均值±标准偏差来表示。组间差异通过学生t检验或单因子方差分析或广义估计方程式进行分析。当ANOVA显示显著性差异时,接着进行TukeyHSD,来判定各平均值间差异的显著性。p值小于0.05时,表示有统计学上的显著性差异。
[实验结果]
<试验例1近视诱导幼龄小鼠巩膜中的内质网应激应答基因的表达变化>
为了评价作为内质网应激应答基因通路的PERK通路、ATF6通路、IRE1通路与儿童近视进展的关联,按照上述[实验方法]的记载来评价模拟儿童近视进展的小鼠的巩膜中的基因表达。
图2示出了3周近视诱导后的眼轴伸长(a)及屈光变化(b),将此时巩膜的基因表达变化表示于图3。另外,将内质网应激应答基因的通路示于图4。其结果,在近视诱导幼龄小鼠的巩膜中,作为内质网应激应答的主要基因(图4)的PERK、ATF6、IRE1的下游的基因表达显著地亢进(图3)。
由这些结果确认到,随着儿童近视进展,PERK通路、ATF6通路、IRE1通路的基因表达会亢进。
<试验例2由内质网应激应答基因的各抑制剂所引起的近视进展抑制>
在试验例1中暗示了PERK、ATF6及IRE1参与了儿童近视进展,因此在该试验例2中,评价近视进展的表型会因这些基因的已知抑制剂而受到何种影响。需要说明的是,作为PERK抑制剂,使用了GSK2656157(GSK)、GSK2606414,作为ATF6抑制剂,使用了甲磺酸奈非那韦水合物(NFV)、Ceapin-A7,作为IRE1抑制剂,使用了STF080312(STF)、4μ8C(图5)。
图6-a、b示出在小鼠的近视诱导期间,将60μM的STF、100μM的GSK、100μM的NFV在10天期间每天滴眼1次之后的眼轴伸长(a)及屈光变化(b)。图6-c、d示出同样地滴眼这些抑制剂的组合(STF+GSK:S+G、GSK+NFV:G+N、NFV+STF:N+S、STF+GSK+NTF:S+G+N)之后的眼轴伸长(c)及屈光变化(d)。另外,图7示出分别同样地滴眼100μM的GSK2606414、Ceapin-A7、4μ8C之后的眼轴伸长(a)及屈光变化(b)。
其结果,在近视诱导幼龄小鼠的巩膜中,通过作为内质网应激应答的主要基因的PERK、ATF6、IRE1各自的抑制剂的单独滴眼,与预测相反,并未观察到眼轴伸长抑制及屈光的近视化的抑制(图6-a、b)。反而通过除STF以外的抑制剂的单独滴眼,未经近视诱导的对照眼的眼轴与DMSO滴眼相比显著伸长,屈光呈近视化。另外,若将这些抑制剂组合进行滴眼,则仅在至少PERK抑制剂与ATF6抑制剂这两种存在时(G+N、S+G+N),眼轴长度显著被抑制,屈光的近视化被抑制,且并未观察到在单独滴眼时观察到的对照眼的眼轴伸长(图6-c、d)。此外,与图6不同的抑制剂GSK2606414、Ceapin-A7、4μ8C单独滴眼所引起的眼轴长度及屈光的变化与图6的结果完全同样,眼轴伸长及屈光近视化均没有被抑制,单独滴眼除4μ8C以外的抑制剂时,就连对照眼的眼轴也伸长(图7)。
由这些结果确认到,内质网应激通路的主要基因(PERK、ATF6、IRE1)之中,在至少抑制PERK与ATF6这两者的情况下,眼轴伸长被抑制,屈光的近视化也被抑制。在PERK单独、ATF6单独、PERK与IRE1、ATF6与IRE1的抑制的情况下,观察到超过与成长相伴的眼轴伸长而导致了病理性眼轴伸长。认为抑制PERK通路与ATF6通路对于抑制近视而言是重要的。另外,虽不予限定,从探索儿童近视进展抑制剂的观点考虑,认为探索可抑制PERK通路与ATF6通路这两者的成分是有效的。
<试验例3 4-PBA及TUDCA引起的内质网应激通路的抑制>
在试验例2中,为了探索儿童近视进展抑制剂,认为探索抑制PERK通路与ATF6通路这两者的成分是有效的,因此在该试验例3中,针对已知会抑制眼轴伸长的成分(苯基丁酸钠{4-PBA}、牛磺熊去氧胆酸{TUDCA}),评价内质网应激通路的抑制分布。
图8示出在整个小鼠的近视诱导期间,每天腹腔注射4-PBA之后的基因表达变化。图9示出由4-PBA施予所引起的近视诱导第1周、第3周的眼轴伸长(a)与屈光变化(b)。另外,图10示出用0.2%与2%4-PBA在近视诱导过程中对小鼠滴眼之后的眼轴伸长(a)与屈光变化(b)。另外,图11示出在整个近视诱导期间,每天腹腔注射TUDCA之后的眼轴伸长(b)与屈光变化(a)。
其结果,在近视诱导幼龄小鼠中,位于已亢进的PERK通路与ATF6通路下游(图4)的基因表达因滴眼2%4-PBA而显著被抑制(图8)。另外,滴眼2%4-PBA第1周与第3周的眼轴伸长,同等程度地显著被抑制,屈光的近视化也同等程度地显著被抑制。另外,与此同时,未经近视诱导的对照眼的眼轴伸长(生理性眼轴伸长)并没有连带受到抑制,而仅抑制了近视诱导眼的病理性眼轴伸长(图9)。此外,比较了0.2%与2%4-PBA的眼轴伸长与屈光变化的结果,观察到用量依赖性的有效性(图10)。另外,同样地,即使施予已知为内质网应激抑制剂的TUDCA,也与4-PBA同样地,并没有抑制生理性眼轴伸长,仅抑制了病理性眼轴伸长(图11)。
由这些结果确认到,4-PBA、TUDCA在内质网应激通路中,通过抑制作为儿童近视进展抑制机制的PERK通路与ATF6通路(图12),并未抑制与正常的眼成长相伴的生理性眼轴伸长,仅抑制病理性眼轴伸长。即确认到,如4-PBA、TUDCA、PERK抑制剂与ATF6抑制剂的组合这样抑制PERK与ATF6这两者的成分可在不妨碍儿童从远视到正视的正常屈光变化的情况下仅抑制超出正常的近视进展。
根据试验例1~3的结果,通过利用模拟人类儿童正视化后接着发生近视进展的近视诱导幼龄小鼠来进行评价,判明了其病理性眼轴伸长的机制(起因于内质网应激的PERK通路与ATF6通路的亢进),发现了基于此的儿童近视进展抑制剂的探索方法。并且确认到,4-PBA及TUDCA不单是具有眼轴伸长抑制效果,而且具有通过抑制PERK通路与ATF6通路在不抑制生理性眼轴伸长的情况下仅抑制病理性眼轴伸长这样的效果。即,在体内确认了PERK通路及ATF6通路的同时抑制剂可适当地预防、治疗儿童近视进展。
<试验例4在抑制儿童近视进展中ATF6通路的参与>
进一步研究了在抑制儿童近视进展中,PERK通路与ATF6通路这两通路之中、ATF6通路以何种程度参与。按照上述[实验方法]的记载,用Western印迹法进行浓度测定分析,求出ATF6的激活态(ATF6-N)量及ATF6的前体态(ATF6-P)量。近视诱导幼龄小鼠的巩膜中的PERK、ATF6、IRE1各自的抑制剂的单独滴眼方法或基于抑制剂的组合的滴眼方法等以试验例2的记载为基准。
以ATF6的激活态(ATF6-N)量除以ATF6的前体态(ATF6-P)量而得的值为激活的指标,示于图13。
如图13所示,ATF6的ATF6-N的量除以ATF6的ATF6-P的量而得的值,在几组中显示显著高的值。尤其是在将两种抑制剂组合的情况下,活性型ATF6显示高值的组,与分别在图6c及图6d所示的观察到病理性眼轴伸长及屈光降低的组一致。即,表明在近视诱导眼(LIM眼)中,ATF6失活时,近视化会被抑制。其相关性可通过比较图6c-d与图13而显示,汇总至下述表1。表1中的“STF”或“S”表示IRE1抑制剂,“GSK”或“G”表示PERK抑制剂,“NFV”或“N”表示ATF6抑制剂,这与前述的试验例同样。表1中汇总的结果表明,在近视眼的巩膜中,ATF6通路的激活成为触发因子而引起与眼轴伸长相伴的屈光降低;反之,通过ATF6通路的失活,与眼轴伸长相伴的屈光降低会受到抑制。对于治疗、预防儿童近视进展而言,具有该药效·药理的药剂(4-PBA)是有效的。
[表1]
<试验例5滴眼剂施予对近视诱导所致的晶状体肥厚的影响>
确认到通过近视诱导(LIM),晶状体有稍微变厚的倾向。对是否会因4-PBA的施予形态的不同而对晶状体的变化带来影响进行了研究。按照上述[实验方法]的记载,对于近视诱导幼龄小鼠滴眼或腹腔内施予4-PBA,与眼轴长度的测量同样地,使用SD-OCT测量晶状体的厚度。
如图14(A)所示,与DMSO滴眼NL(=无透镜)组相比,-30D透镜佩戴组中,观察到晶状体因为近视诱导(LIM)而变厚。在腹腔内施予4-PBA时,未对晶状体的肥厚造成影响。另一方面,如图14(B)所示,在通过滴眼施予4-PBA时,-30D透镜佩戴组中并未观察到晶状体的肥厚。即表明作为4-PBA的施予方法,从对目标组织的到达性的观点考虑,滴眼是适宜的。
Claims (7)
1.抑制儿童近视进展用滴眼剂,其含有PERK(PKRK-样内质网激酶)通路及/或ATF6(转录激活因子6)通路的抑制剂作为有效成分。
2.如权利要求1所述的滴眼剂,其中,所述抑制剂为选自由苯基丁酸及其药理学上容许的盐组成的组中的至少一种。
3.如权利要求1或2所述的滴眼剂,其中,所述抑制剂为苯基丁酸钠。
4.如权利要求1~3中任一项所述的滴眼剂,其中,所述抑制剂的含量相对于滴眼剂总量而言为0.01~5质量%。
5.如权利要求1~4中任一项所述的滴眼剂,其中,所述抑制儿童近视进展不会抑制生理性眼轴伸长。
6.如权利要求1~5中任一项所述的滴眼剂,其中,所述抑制儿童近视进展对病理性眼轴伸长进行抑制。
7.儿童近视进展抑制剂的筛选方法,所述筛选方法包括:使候选物质接触源自眼的细胞的工序;和以所述细胞中的、PERK及/或ATF6的信号转导系统的蛋白质及/或基因的变化为指标来选择候选物质的工序。
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CN107898793B (zh) * | 2017-12-01 | 2019-12-24 | 温州医科大学 | 一种抑制近视的方法及制备药物的应用 |
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PE20240227A1 (es) | 2024-02-16 |
AU2021396680A1 (en) | 2023-07-06 |
CA3204753A1 (en) | 2022-06-16 |
AU2021396680A9 (en) | 2024-05-30 |
MX2023006723A (es) | 2023-09-21 |
MA61683A1 (fr) | 2023-08-31 |
WO2022123836A1 (ja) | 2022-06-16 |
JPWO2022123836A1 (zh) | 2022-06-16 |
US20240041806A1 (en) | 2024-02-08 |
EP4257147A1 (en) | 2023-10-11 |
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