Cyclodextrins as potential treatment for age related macular degeneration.

环糊精作为年龄相关性黄斑变性的潜在治疗方法。

• 批准号: 8445856
• 负责人: Enrique J Rodriguez-Boulan
• 金额: $ 21.13万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445856
• 关键词: Affect; Affinity; Age; Age related macular degeneration; Animal Model; Basal lamina; Binding; Biological Assay; Blindness; Cells; Cessation of life; Chemistry; Complex; Computers; Cyclodextrins; Data; Deposition; Disease; Drusen; Effectiveness; Elderly; Encapsulated; Equilibrium; Etiology; Exocytosis; Family; Genetic; Glucose; Hereditary Disease; In Vitro; Lipids; Lipofuscin; Lysosomes; Mannose; Mediating; Membrane; Molecular Models; Mus; Nonexudative age-related macular degeneration; Other Genetics; Palliative Care; Pathogenesis; Penetration; Pharmaceutical Preparations; Population; Preclinical Drug Evaluation; Refractory; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Role; Site; Stargardt' s disease; Structure of retinal pigment epithelium; Testing; Therapeutic Agents; Vitelliform macular dystrophy; base; beta-Cyclodextrins; betadex; design; improved; in vivo; inorganic phosphate; insight; molecular modeling; mouse model; novel; oxidation; prevent; public health relevance; receptor; research study; retinal rods; tool; uptake

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.

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，用于治疗与年龄相关的黄斑变性（AMD）和相关的遗传苦难Stargardt病（SD）和最佳疾病（BD）。 AMD是美国老年人无法治愈的失明的第一大原因。尽管姑息治疗可用于湿AMD，但尚无干燥AMD的治疗方法，即最常见的疾病形式（90％的病例）。越来越多的证据表明，在AMD，SD和BD的发病机理中，脂肪霉素双素（LBS）的异常积累。由于LBS对降解是难治性的，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行，并且是不可逆的。超过阈值，LB会导致RPE细胞故障和死亡，因此相关杆和锥形感光体死亡。因此，非常需要从RPE中去除LB的药物。我们最近开发了一种测定法，以筛选与主要脂肪蛋白双反霉素A2E相互作用的药物，并使用该测定法鉴定一组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。我们的具体目的是：（1）测试我们领先的CD在防止RPE中LBS积累引起的AMD模型中预防视网膜变性的有效性； （2）研究CD的作用机理和（3）开发具有对LBS亲和力增加的CD，并增强了穿透RPE溶酶体的能力。这些实验可能会提供有关AMD发病机理的见解，并可能导致一种新型药物来治疗干AMD，Stargardt疾病和最佳疾病，目前尚无治疗。