JP2023017050A - マウス近視誘導モデル及び近視予防・抑制のための小胞体ストレス抑制剤 - Google Patents
マウス近視誘導モデル及び近視予防・抑制のための小胞体ストレス抑制剤 Download PDFInfo
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- JP2023017050A JP2023017050A JP2022197027A JP2022197027A JP2023017050A JP 2023017050 A JP2023017050 A JP 2023017050A JP 2022197027 A JP2022197027 A JP 2022197027A JP 2022197027 A JP2022197027 A JP 2022197027A JP 2023017050 A JP2023017050 A JP 2023017050A
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Abstract
Description
(1)小胞体ストレス抑制剤を有効成分として含有することを特徴とする近視予防・抑制剤。
(2)前記小胞体ストレス抑制剤がフェニル酪酸、タウロウルソデオキシコール酸、サルブリナル、グアナベンツ、GSK2606414、GSK2656157、ISRIB、アゾラミド、アークティゲニン又はそれらの薬理学的に許容される塩であることを特徴とする(1)記載の近視予防・抑制剤。
(3)前記小胞体ストレス抑制剤がフェニル酪酸、タウロウルソデオキシコール酸、又はそれらの薬理学的に許容される塩であることを特徴とする(1)又は(2)記載の近視予防・抑制剤。
(4)前記近視が軸性近視であることを特徴とする(1)~(3)いずれか1つ記載の近視予防・抑制剤。
(5)前記近視が病的近視であることを特徴とする(1)~(4)いずれか1つ記載の近視予防・抑制剤。
(6)剤形が点眼剤であることを特徴とする(1)~(5)いずれか1つ記載の近視予防・抑制剤。
(7)プロテクター及びマイナスレンズを幼若マウスの眼前に装着し、マウスの成長に応じて調節機構により角度及び幅を調節して飼育することを特徴とするマウス近視誘導モデル作製方法。
(8)プロテクター及びマイナスレンズを幼若マウスの眼前に装着し、マウスの成長に応じて調節機構により角度及び幅を調節し近視誘導を行うマウスモデルに、候補物質を投与することを特徴とする近視予防・抑制医薬スクリーニング方法。
(9)プロテクター及びマイナスレンズを幼若マウスの眼前に装着し、マウスの成長に応じて調節機構により角度及び幅を調節して飼育することにより作製されたマウス近視誘導モデル。
まず、本発明のマウスモデルの作製方法について説明を行う。マイナスレンズを装用させて軸性近視が誘導される機構を図1に模式的に示している。正眼視は目に入ってくる平行光線が網膜上で像を結ぶことから、像がはっきりと見える状態をいう。一方、軸性近視は、眼軸長が長くなっているために目に入ってくる平行光線が網膜の手前で像を結ぶため、はっきりと見えない状態をいう。ヒトを含め、動物の眼は成長とともに大きくなる。幼若なマウスにマイナスレンズを装用させると、マイナスレンズを装用しているときに像を結ぶ位置、すなわちマイナスレンズ装用時にはっきりと見える状態まで眼軸が伸長する。その結果、眼軸が伸長し、軸性近視と同様の眼の状態を作り出すことができる。
近視誘導モデルの病態を詳細に調べるために、透過型電子顕微鏡(TEM)を用いて解析を行った。3週間マイナスレンズを装用させ軸性近視を誘導した眼球、及びコントロールとしてフレームのみを装用させていた眼球をマウスから摘出し、2.5%グルタールアルデヒド/生理食塩水で1時間、4℃で固定した。角膜を除去し、2.5%グルタールアルデヒド/生理食塩水で一晩、後固定を行い、Epok812(応研商事株式会社)で包埋し薄切しTEM(JEM-1400plus、日本電子株式会社)により観察した。図3の上段にコントロール、下段に-30Dレンズを装用させて近視誘導を行ったマウスから得た試料の強膜を示す。スケールは左から1.0μm、500nm、500nmである。
電子顕微鏡の観察結果から、近視誘導に伴って小胞体ストレスが生じていることが示唆された。そこで、小胞体ストレス抑制剤を投与し、近視誘導が抑制されるか解析を行った。小胞体ストレス抑制剤として、フェニル酪酸ナトリウム(Cayman株式会社)200mg/kg/dayの用量で、レンズ装用後2日目から21日目まで毎日腹腔内投与を行い、21日目に屈折値、眼軸長を測定した。なお、コントロール群には、PBSのみを投与した。
次に、同じく小胞体ストレス抑制剤として知られているタウロウルソデオキシコール酸の効果の解析を行った。実施例1と同様に、3週齢雄性C57BL6Jマウスを用いて解析を行った。マウスは右眼に-30Dのレンズを左眼にはフレームのみを装用した。レンズ装用当日から100mg/kg タウロウルソデオキシコール酸(SIGMA-Aldrich株式会社)を腹腔内投与により1日1回投与し(n=4)、対照群(n=4)にはPBSを等量腹腔内投与した。レンズ装用前、装用1週間後に眼軸長・屈折値を測定し、その変化量を算出した。図5左には屈折値を、右には眼軸長の変化を示す。
近視を抑制する薬剤として、点眼剤、あるいは眼軟膏のように直接目に投与することのできる剤形は、高い効果が望める点、また、患者自らが投与できることから望ましい。そこで、実施例1と同様にしてマウス近視誘導モデルを作製し、フェニル酪酸ナトリウムの点眼による効果を解析した。
上記で示したように、小胞体ストレスの抑制剤が近視誘導に対して抑制効果があることから、小胞体ストレスが近視誘導に直接的に関与しているものと考えられる。そこで、小胞体ストレスを誘導する薬剤を投与することによって、近視を誘導することができるか解析を行った。対象は3週齢雄性C57BL6Jマウス(n=12)とした。マウスには右眼に50μg/mlのツニカマイシン(Tm)(SIGMA Aldrich株式会社)又は10μMのタプシガルギン(TG)(和光純薬工業株式会社)、左眼にはPBS(Veh)を1回点眼投与した。ツニカマイシン、タプシガルギン投与前および1週間後に屈折値、及び眼軸長を測定し、その変化量を算出した(図7)。
上述のように、小胞体ストレスの下流には、IRE1経路、PERK経路、ATF6経路の3つの経路があることが知られている。小胞体ストレス経路の3つの経路の阻害剤を用いて、近視誘導抑制効果があるか解析を行った。
Claims (8)
- 小胞体ストレス自体を抑制する薬剤を有効成分として含有する、近視の予防、治療、又は抑制剤。
- PERK経路及び/又はATF6経路を阻害する薬剤を有効成分として含有する、近視の予防、治療、又は抑制剤。
- 剤形が点眼剤である、請求項1又は2記載の近視の予防、治療、又は抑制剤。
- 前記有効成分の含有量が、0.2質量%~2質量%である、請求項1~3のいずれか1項に記載の近視の予防、治療、又は抑制剤。
- 1日1回投与されるものである、請求項1~4のいずれか1項に記載の近視の予防、治療、又は抑制剤。
- 3週間以上投与されるものである、請求項1~5のいずれか1項に記載の近視の予防、治療、又は抑制剤。
- 成長に付随して生じる正常な眼軸長の伸長期間に投与されるための、請求項1~6のいずれか1項に記載の近視の予防、治療、又は抑制剤。
- 小児用である、請求項1~7のいずれか1項に記載の近視の予防、治療、又は抑制剤。
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