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用于治疗年龄相关性黄斑变性（AMD）和相关遗传性疾病Stargardt病（SD）和Best病（BD）的小型药物方法。AMD是美国老年人中无法治愈的失明的头号原因。虽然姑息疗法可用于湿性AMD，但没有可用于干性AMD的治疗，干性AMD是该疾病最常见的形式（90%的病例）。越来越多的证据表明，脂褐素双维甲酸（LB）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LB难以降解，并且RPE细胞不分裂，因此它们在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。超过阈值，LB导致RPE细胞功能障碍和死亡，随之而来的是相关的视杆和视锥光感受器的死亡。因此，非常需要从RPE中去除LB的药物。我们最近开发了一种检测方法来筛选与主要脂褐质双维A酸A2 E相互作用的药物，并使用该检测方法来鉴定一组A2 E相互作用药物，即环糊精（CD）。我们的实验表明，一些商业CD增溶A2 E，防止其氧化并降低培养的RPE细胞中的A2 E水平。我们的具体目标是：（1）测试我们的主要CD在预防由RPE中LB积累引起的AMD小鼠模型中的视网膜变性中的有效性;（2）研究CD的作用机制和（3）开发对LB具有增加的亲和力和增强的穿透RPE溶酶体的能力的CD。这些实验可能提供关于AMD发病机制的见解，并可能导致一种新的药物来治疗干性AMD，Stargardt病和Best病，目前没有治疗方法。

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.