Cyclodextrins as potential treatment for age related macular degeneration.

描述（由申请人提供）：我们的长期目标是开发一种小型药物方法来治疗年龄相关性黄斑变性（AMD）以及相关的遗传性疾病Stargardt病（SD）和Best病（BD）。在美国，老年性黄斑变性是导致老年人无法治愈的失明的头号原因。尽管对湿性黄斑变性有姑息性治疗，但对最常见的干性黄斑变性（90%的病例）尚无治疗方法。越来越多的证据表明，脂褐素类双维甲酸（LBs）在视网膜色素上皮（RPE）中的异常积累与AMD、SD和BD的发病机制有关。由于LBs难以降解，RPE细胞不分裂，它们在RPE溶酶体中的积累随着年龄的增长而进展，并且是不可逆的。超过一定阈值，LBs会导致RPE细胞功能障碍和死亡，随之而来的是相关的杆状和锥状光感受器的死亡。因此，对从RPE中去除LBs的药物有很大的需求。我们最近开发了一种检测方法来筛选与主要脂褐素双维甲酸A2E相互作用的药物，并使用该检测方法鉴定了一组与A2E相互作用的药物，即环糊精（CD）。我们的实验表明，一些商业cd可以溶解A2E，防止其氧化并降低培养的RPE细胞中的A2E水平。我们的具体目标是：(1)在RPE中积聚LBs引起的AMD小鼠模型中，测试我们领先的CDs在预防视网膜变性方面的有效性；(2)研究CDs的作用机制；(3)开发对LBs亲和力增强、穿透RPE溶酶体能力增强的CDs。这些实验可能为AMD的发病机制提供新的见解，并可能产生一种新的药物来治疗目前尚无治疗方法的干性AMD、Stargardt病和Best病。

DESCRIPTION (provided by applicant): Our long-term objective is to develop a small drug approach for the treatment of Age related Macular Degeneration (AMD) and the related genetic afflictions Stargardt Disease (SD) and Best Disease (BD). AMD is the number one cause of incurable blindness among older adults in the US. Although a palliative therapy is available for wet AMD, there is no treatment available for dry AMD, the most frequent form of the disease (90% of the cases). Growing evidence implicates the abnormal accumulation of lipofuscin bisretinoids (LBs) in the retinal pigment epithelium (RPE) in the pathogenesis of AMD, SD and BD. As LBs are refractory to degradation and RPE cells do not divide, their accumulation in RPE lysosomes progresses with age and is irreversible. Beyond a threshold, LBs cause RPE cell malfunction and death, with consequent death of associated rod and cone photoreceptors. Hence, there is a great need for drugs that remove LBs from RPE. We have recently developed an assay to screen drugs that interact with the major lipofuscin bisretinoid A2E and used this assay to identify a group of A2E-interacting drugs, the cyclodextrins (CD). Our experiments show that some commercial CDs solubilize A2E, prevent its oxidation and reduce A2E levels in cultured RPE cell. Our specific aims are: (1) to test the effectiveness of our leading CDs in preventing retinal degeneration in a mouse model of AMD caused by accumulation of LBs in RPE; (2) to study the mechanism of action of CDs and (3) to develop CDs with increased affinity for LBs and enhanced ability to penetrate RPE lysosomes. These experiments may provide insights on the pathogenesis of AMD and may result in a new kind of drugs to treat dry-AMD, Stargardt Disease and Best Disease, for which no treatment is currently available.