Department of Ophthalmology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Invest Ophthalmol Vis Sci. 2013 Jan 17;54(1):455-66. doi: 10.1167/iovs.12-11152.
Investigate whether retinas of mice with impaired retinal cycles exposed to light or kept in the dark tolerate prolonged high-dose administration of QLT091001, which contains as an active ingredient, the 9-cis-retinal precursor, 9-cis-retinyl acetate.
Four- to six-week-old Lrat(-/-) and Rpe65(-/-) mice (n = 126) as well as crossbred Gnat1(-/-) mice lacking rod phototransduction (n = 110) were gavaged weekly for 6 months with 50 mg/kg QLT091001, either after being kept in the dark or after light bleaching for 30 min/wk followed by maintenance in a 12-hour light ≤ 10 lux)/12-hour dark cycle. Retinal health was monitored by spectral-domain optical coherent tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) every other month and histological, biochemical, and visual functional analyses were performed at the end of the experiment. Two-photon microscopy (TPM) was used to observe retinoid-containing retinosome structures in the RPE.
Retinal thickness and morphology examined by SD-OCT were well maintained in all strains treated with QLT091001. No significant increases of fundus autofluorescence were detected by SLO imaging of any strain. Accumulation of all-trans-retinyl esters varied with genetic background, types of administered compounds and lighting conditions but retinal health was not compromised. TPM imaging clearly revealed maintenance of retinosomes in the RPE of all mouse strains tested.
Retinas of Lrat(-/-), Rpe65(-/-), and crossbred Gnat1(-/-) mice tolerated prolonged high-dose QLT091001 treatment well.
研究在光暴露或暗适应下，视网膜周期受损的小鼠视网膜是否能耐受长时间大剂量 QLT091001 给药，该药物含有作为活性成分的 9-顺式视黄醛前体 9-顺式视黄基乙酸酯。
4 至 6 周龄的 Lrat(-/-)和 Rpe65(-/-)小鼠（n=126）以及缺乏杆状光转导的杂交 Gnat1(-/-)小鼠（n=110）每周通过灌胃接受 50mg/kg 的 QLT091001 治疗，共 6 个月，要么在暗适应下进行，要么在每周光漂白 30 分钟后，维持 12 小时光强度≤10lux/12 小时暗循环。每隔一个月通过光谱域光学相干断层扫描（SD-OCT）和扫描激光检眼镜（SLO）监测视网膜健康状况，并在实验结束时进行组织学、生物化学和视觉功能分析。使用双光子显微镜（TPM）观察 RPE 中含有类视黄醇的视黄醇体结构。
SD-OCT 检查的视网膜厚度和形态在所有接受 QLT091001 治疗的品系中均得到良好维持。SLO 成像未检测到任何品系的眼底自发荧光显著增加。所有-trans-视黄基酯的积累随遗传背景、给药化合物的类型和光照条件而变化，但视网膜健康状况并未受损。TPM 成像清楚地显示，所有测试的小鼠品系的 RPE 中均维持了视黄醇体。
Lrat(-/-)、Rpe65(-/-)和杂交 Gnat1(-/-)小鼠的视网膜能耐受长时间大剂量 QLT091001 治疗。
