Retinal-chitosan Conjugates Effectively Deliver Active Chromophores to Retinal Photoreceptor Cells in Blind Mice and Dogs
Retinal-chitosan Conjugates Effectively Deliver Active Chromophores to Retinal Photoreceptor Cells in Blind Mice and Dogs
复制标题
DOI：
10.1124/mol.117.111294
复制
发表时间：
2018-05-01
影响因子：
3.6
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
--
作者：
Gao, Songqi;Kahremany, Shirin;Palczewski, Krzysztof
类维生素A（视觉）循环由再生视觉发色团11-顺式-视网膜和维持视力所需的一系列生化反应组成。影响发色团产生的遗传或环境因素可能导致失明。我们之前使用模拟人类视网膜疾病的动物模型证明，基于机制的药物干预可以在无法治愈的视网膜遗传疾病中维持视力。在这里，我们报告给卵磷脂：视黄醇酰基转移酶缺陷（Lrat（-/-））小鼠施用9-顺式视黄醛后，药物被迅速吸收，然后在1至2小时内被清除。然而，当缀合形成壳聚糖-9-顺-视黄醛时，这种前药从胃肠道缓慢吸收，导致9-顺-视黄醇的血浆水平可持续并恢复视功能，而不会像未缀合药物治疗时那样引起水平升高。通过视网膜电图检查评估，在视网膜色素上皮特异性 65 类视黄醇异构酶 (RPE65) 缺陷的狗中，玻璃体内注射壳聚糖-9-顺式-视网膜缀合物可改善光感受器功能。功能性挽救是剂量依赖性的并维持数周。通过犬科动物胃肠道给药被发现无效，很可能是由于犬科动物维生素 A 血液运输的特殊性。将壳聚糖缀合物与 11-cis-6-ring-retinal（一种 11-cisretinal 的锁环类似物）结合使用，可以选择性地阻止视杆细胞视蛋白对生色团的消耗，同时很大程度上保留视锥细胞视蛋白，可延长 Lrat(-/-) 小鼠的视锥视觉。开发这种组合低剂量方案来选择性地延长有用的锥视力不仅可以扩大视网膜疾病的治疗范围，包括莱伯先天性黑蒙，还可以治疗由于进行性视黄醇循环缺乏而导致的与年龄相关的人类暗适应能力的下降。
The retinoid (visual) cycle consists of a series of biochemical reactions needed to regenerate the visual chromophore 11-cis-retinal and sustain vision. Genetic or environmental factors affecting chromophore production can lead to blindness. Using animal models that mimic human retinal diseases, we previously demonstrated that mechanism-based pharmacological interventions can maintain vision in otherwise incurable genetic diseases of the retina. Here, we report that after 9-cis-retinal administration to lecithin: retinol acyltrans-ferase-deficient (Lrat(-/-)) mice, the drug was rapidly absorbed and then cleared within 1 to 2 hours. However, when conjugated to form chitosan-9-cis-retinal, this prodrug was slowly absorbed from the gastrointestinal tract, resulting in sustainable plasma levels of 9-cis-retinol and recovery of visual function without causing elevated levels, as occurs with unconjugated drug treatment. Administration of chitosan-9-cis-retinal conjugate intravitreally in retinal pigment epithelium-specific 65 retinoid isomerase (RPE65)-deficient dogs improved photoreceptor function as assessed by electroretinography. Functional rescue was dose dependent and maintained for several weeks. Dosing via the gastrointestinal tract in canines was found ineffective, most likely due to peculiarities of vitamin A blood transport in canines. Use of the chitosan conjugate in combination with 11-cis-6-ring-retinal, a locked ring analog of 11-cisretinal that selectively blocks rod opsin consumption of chromophore while largely sparing cone opsins, was found to prolong cone vision in Lrat(-/-) mice. Development of such combination low-dose regimens to selectively prolong useful cone vision could not only expand retinal disease treatments to include Leber congenital amaurosis but also the age-related decline in human dark adaptation from progressive retinoid cycle deficiency.