Cyclodextrins as potential treatment for age related macular degeneration.

描述(申请人提供)：我们的长期目标是开发一种治疗老年性黄斑变性(AMD)和相关的遗传性疾病Stargardt病(SD)和Best病(BD)的小药物方法。AMD是美国老年人无法治愈的失明的头号原因。虽然湿性AMD有姑息疗法，但干性AMD没有治疗方法，干性AMD是最常见的疾病形式(90%)。越来越多的证据表明，在AMD、SD和BD的发病机制中，视网膜色素上皮(RPE)中脂褐素双维A酸类化合物(LBS)异常堆积。由于LBS不易降解，RPE细胞不分裂，其在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。超过阈值，LBS会导致RPE细胞故障和死亡，从而导致相关的视杆和视锥感光细胞死亡。因此，对从RPE中去除LBS的药物的需求很大。我们最近开发了一种方法来筛选与主要的脂褐素双维A酸A2E相互作用的药物，并使用这种方法来鉴定一组与A2E相互作用的药物，环糊精(CD)。我们的实验表明，一些商品化的镉可以溶解A2E，防止其氧化，降低培养的RPE细胞中A2E的水平。我们的具体目标是：(1)测试我们领先的CDS在防止由于LBS在RPE中积聚而导致的AMD小鼠模型视网膜退化方面的有效性；(2)研究CDS的作用机制；以及(3)开发对LBS的亲和力增强、穿透RPE溶酶体的能力增强的CDS。这些实验可能为AMD的发病机制提供见解，并可能导致一种治疗干性AMD、Stargardt病和Best疾病的新药，目前尚无治疗方法。

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.