Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma

青光眼是一种眼部神经退行性疾病，估计患病率为8千万患者 到2020年，全球至少有600万到800万人成为双眼失明。眼内压（IOP）升高 导致视神经轴突变性和视网膜神经节细胞（RGC）的进行性丧失 这是青光眼的特征性标志。临床上，唯一能减缓昏迷的方法 视力丧失是为了降低眼内压（IOP），这是部分有效的，并没有解决 RGC变性的易感性。目前青光眼的治疗包括使用前列腺素类似物 然而，大约10%的青光眼患者对这些治疗没有反应。 溴莫尼定是一种α2激动剂，滴眼液可降低IOP，也具有神经保护作用，但它会引起许多 副作用，如过敏反应和角膜疾病。沿着IOP，年龄相关的抗- 眼组织中的氧化酶导致RGCs和小梁网（TM）的死亡 细胞，这是没有解决的现有治疗。一氧化氮（NO）系统可能是 靶向通过松弛小梁网（TM）细胞以降低IOP来增强房水流出。 在这里，我们建议开发一种稳健的混合NO供体和SOD模拟化合物， PLGA纳米粒可延长降眼压的持续时间，并具有神经保护作用。 我们合成了一种新型的具有NO供体和SOD模拟物的双功能杂化化合物SA-2 官能团。我们的初步结果表明，一个单一的眼滴PLGA封装， SA-2纳米颗粒（SA-2-NPs）在小鼠青光眼模型中降低IOP 50%。此外，本发明还 化合物SA-2在成年大鼠视网膜外植体的离体缺氧损伤中具有高度的神经保护作用， 在体小鼠视神经玻璃体内注射损伤模型。我们的目标是1）优化剂量 通过SA-2-NP的毒代动力学研究，并确定在两种动物模型中降低IOP的功效： 用Ad5.TGFβ2诱导的小鼠高眼压模型和正常猴眼高眼压模型。 2)为了阐明化合物SA-2保护人TM和人TM的生化机制， 细胞和视网膜节细胞。3)为了评估局部施用的SA-2-NP的 在两种模型中防止RGC死亡的能力：视神经挤压（创伤性损伤）的小鼠模型和 高眼压（慢性损伤）小鼠模型。顺利完成上述提议 研究将提供有关SA-2-NP最大有效剂量和给药频率的信息 作为我们未来的目标，将在激光诱导的OHTN猴模型中进一步评估，并最终将 人类临床试验的进展。研究结果将对该领域产生重大影响， 开发新的非前列腺素治疗剂， 方面的影响.

Glaucoma is a neurodegenerative disease of the eye with an estimated prevalence of 80 million patients worldwide by 2020, at least 6 to 8 million becoming bilaterally blind. Elevated intraocular pressure (IOP) causing axonal degeneration of the optic nerve and progressive loss of retinal ganglion cells (RGCs) which are the characteristic hallmarks of glaucoma. Clinically, the only method of slowing glaucomatous vision loss is to reduce intraocular pressure (IOP), which is partially effective and doesn’t address susceptibility to RGC degeneration. Current therapy for glaucoma includes use of prostaglandin analogs based IOP lowering agents, however, about 10% of glaucoma patients don’t respond to these therapies. Brimonidine, an α2 agonist, eye-drop lowers IOP and is also neuroprotective, however it causes many side effects such as allergic reactions and corneal disorders. Along with IOP, age related decline in anti- oxidant enzymes in ocular tissues contributes to the death of both RGCs and trabecular meshwork (TM) cells, which is not addressed by available treatments. The nitric oxide (NO) system could potentially be targeted to enhance the aqueous outflow by relaxing the trabecular meshwork (TM) cells to lower IOP. Here, we propose to develop a robust hybrid NO donating and SOD mimetic compound encapsulated in PLGA nanoparticle which will prolong the duration of lowering IOP and also have neuroprotective effects. We have synthesized a novel bi-functional hybrid compound SA-2 with NO donor and SOD mimetic functional groups. Our preliminary results demonstrated that, a single eye drop of PLGA encapsulated SA-2 nanoparticles (SA-2-NPs) lowered IOP by 50% in a mouse glaucoma model. Additionally, compound SA-2 is highly neuroprotective both in ex vivo hypoxic insult of adult rat retinal explants and in in vivo mouse optic nerve crush model via intravitreal injection. Our goals are 1) to optimize the dose via toxicokinetic study of SA-2-NPs and determine the efficacy to lower IOP in two animal models: a mouse model of ocular hypertension (OHTN) induced by Ad5.TGFβ2 and in normotensive monkey eyes. 2) To delineate the biochemical mechanisms through which compound SA-2 protects both human TM cells and RGCs from glaucomatous changes. 3) To assess the topically administered SA-2-NPs for their ability to prevent RGC death in two models: a mouse model of optic nerve crush (traumatic injury) and a mouse model of ocular hypertension (chronic injury). Successful completion of the above proposed studies will provide information on the maximum effective dose of and frequency of dosing of SA-2-NPs that will be further evaluated in laser induced OHTN monkey model as our future goal and eventually will progress to human clinical trials. The results will have a major impact in the field with implications for developing novel non-prostaglandin therapeutics that have both IOP lowering and neuroprotective effects.