Aminosterols as Anti-angiogenic Therapeutics for AMD
氨基甾醇作为 AMD 的抗血管生成疗法
基本信息
- 批准号:6834339
- 负责人:
- 金额:$ 10万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-09-01 至 2006-08-31
- 项目状态:已结题
- 来源:
- 关键词:aginganalogangiogenesis inhibitorsbiological signal transductioncholestane compounddrug design /synthesis /productiondrug screening /evaluationeye disorder chemotherapyeye pharmacologyhuman tissueimmunoprecipitationintegrinsintraperitoneal injectionslaboratory ratmacular degenerationnonhuman therapy evaluationpharmacokineticsprotein structure functionvascular endothelial growth factorsvascular endotheliumwestern blottings
项目摘要
Age-related macular degeneration (AMD) is a public health problem resulting in the loss of independence in a significant number of the elderly population. The most severe form of AMD, wet AMD, is caused by the formation of new blood vessels in the choroidal region. Repeated blood leakage from these vessels damages the macula, thereby resulting in rapid irreversible vision loss. Several experimental therapeutics aimed at curtailing angiogenesis had been successful in treating wet AMD in clinical trials. However, these agents require intravitreal injections which present a significant risk of introducing infections and injuries to the eyes. Squalamine, a systemically delivered antiangiogenic aminosterol, had been shown to
preserve/improve vision in 100% of patients 4 months following therapy in a phase 1/11clinical trial. Encouraged by these results, Genaera is seeking to explore squalamine analogs which may have higher potency, simpler synthesis scheme and better pharmacokinetic profile for their application in treating wet AMD. Two analogs that fit these criteria had been identified. The specific aims for this proposal are: 1. To evaluate the in vivo efficacy of squalamine and lead analogs in a rat model of choroidal neovascularization. CNV will be induced in rats by subretinal injection of Matrigel. Squalamine and analogs will be adminstered intraperitoneally daily followed by evaluation of CNV formation at the end of the studies. Studies will be carried out to evaluate squalamine and analogs' ability to prevent the formation of CNV and to regress pre-existing CNV. 2. To determine the effect of squalamine and analogs on VEGF signal transduction and
integrin activity in endothelial cells. Coimmunoprecipitation and Western blotting with phosphospecific antibodies will be used to pinpoint squlamine and analogs' interference on these signaling events. The long term objective of this development program is to identify and refine safe and effective antiangiogenic aminosterols for the treatment of AMD.
老年性黄斑变性(AMD)是一种公共卫生问题,导致相当数量的老年人口丧失独立性。最严重的AMD,湿性AMD,是由脉络膜区域新血管形成引起的。从这些血管反复渗漏的血液损害黄斑,从而导致迅速的不可逆转的视力丧失。几种旨在抑制血管生成的实验疗法在临床试验中成功地治疗了湿性AMD。然而,这些药物需要玻璃体内注射,这对眼睛造成感染和伤害的风险很大。角鲨胺是一种系统释放的抗血管生成氨基甾醇,已被证明
在1/11期临床试验中,100%的患者在治疗4个月后保持/改善视力。受到这些结果的鼓舞,Genaera正在寻求探索可能具有更高效力、更简单的合成方案和更好的药代动力学特征的角鲨胺类似物,用于治疗湿性AMD。已经确定了两个符合这些标准的类似物。该建议的具体目的是:1.评价角鲨胺和铅类似物在脉络膜新生血管模型中的体内疗效。大鼠视网膜下注射Matrigel可诱发CNV。角鲨胺及其类似物将每天给药,然后在研究结束时评估新生血管的形成。将开展研究,评估角鲨胺及其类似物预防CNV形成和逆转先前存在的CNV的能力。2.研究角鲨胺及其类似物对血管内皮细胞生长因子信号转导通路的影响。
内皮细胞中的整合素活性。免疫共沉淀和蛋白印迹与磷酸特异性抗体将被用来精确地确定SQULAM及其类似物对这些信号事件的干扰。这一开发计划的长期目标是识别和提炼安全有效的抗血管生成氨基类固醇治疗AMD。
项目成果
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- 资助金额:
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