Aminosterols as Anti-angiogenic Therapeutics for AMD

视网膜相关性黄斑变性（AMD）是导致相当数量的老年人口丧失独立性的公共卫生问题。最严重的AMD形式，湿性AMD，是由脉络膜区域中新血管的形成引起的。这些血管的反复血液渗漏会损害黄斑，从而导致快速的不可逆视力丧失。几种旨在减少血管生成的实验性疗法已在临床试验中成功治疗湿性AMD。然而，这些药剂需要玻璃体内注射，这存在将感染和损伤引入眼睛的显著风险。角鲨胺是一种全身性的抗血管生成氨基甾醇， 在1/11期临床试验中，治疗后4个月，100%的患者保持/改善视力。受这些结果的鼓舞，Genaera正在寻求探索角鲨胺类似物，这些类似物可能具有更高的效力，更简单的合成方案和更好的药代动力学特征，用于治疗湿性AMD。已经鉴定出符合这些标准的两种类似物。该提案的具体目标是：1.评价角鲨胺和铅类似物在脉络膜新生血管大鼠模型中的体内疗效。通过视网膜下注射Matrigel在大鼠中诱导CNV。角鲨胺和类似物将每天腹膜内施用，然后在研究结束时评价CNV形成。将进行研究以评估角鲨胺和类似物预防CNV形成和消退预先存在的CNV的能力。2.为了确定角鲨胺和类似物对VEGF信号转导和细胞增殖的影响， 内皮细胞中的整合素活性。免疫共沉淀和蛋白质印迹与磷酸特异性抗体将被用来查明这些信号传导事件的SQULAMINE和类似物的干扰。该开发项目的长期目标是确定和改进用于治疗AMD的安全有效的抗血管生成氨基骨水泥。

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.