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

具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼

基本信息

批准号：
9887870
负责人：
Suchismita Acharya
金额：
$ 36.5万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9887870
关键词：
3-nitrotyrosine Address Adult Affect African Green Monkey Aftercare Allergic Reaction Animal Model Anterior Antioxidants Apoptotic Aqueous Humor Bilateral Bioavailable Biochemical Biological Availability Blindness Brimodine Cell Death Cell Survival Cells Cessation of life Characteristics Chronic Clinical Clinical Trials Collaborations Corneal Diseases Cytoskeleton Disease Dose Drug Delivery Systems Drug Kinetics Electroretinography Encapsulated Esters Eye Eye diseases Eyedrops FDA approved Formulation Free Radicals Frequencies Future Gene Expression Glaucoma Global Change Goals Homeostasis Human Hybrids Hypoxia Injury Lasers Latanoprost Lipid Peroxidation Measures Mediating Methods Modeling Monkeys Mus Nature Nerve Crush Neurodegenerative Disorders Nitrates Nitric Oxide Nitric Oxide Donors Ocular Hypertension Optic Nerve Optical Coherence Tomography Pathology Pathway interactions Patients Pattern Physiologic Intraocular Pressure Polymers Posterior eyeball segment structure Predisposition Prevalence Primary Open Angle Glaucoma Production Rattus Reactive Oxygen Species Regulation Retina Retinal Ganglion Cells Rodent Rodent Model Route Safety Sulfhydryl Compounds Synthetic Prostaglandins System Testing Therapeutic Tissues Topical application Toxic effect Toxicokinetics Trabecular meshwork structure Traumatic injury Venous Pressure level age related alpha 2 agonist antioxidant enzyme aqueous axonal degeneration base blind drug release profile functional group in vivo intravitreal injection mimetics mouse model nanoparticle nanoparticle drug neuroprotection normotensive novel novel therapeutics patient population preservation pressure prevent retinal ganglion cell degeneration safety assessment side effect small molecule stem transcriptome sequencing treatment effect

项目摘要

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.

青光眼是一种眼部神经退行性疾病，估计有 8000 万患者患病到 2020 年，全球至少有 6 至 800 万人双眼失明。眼压升高（IOP）导致视神经轴突变性和视网膜神经节细胞（RGC）逐渐丧失这是青光眼的特征性特征。临床上，唯一减缓青光眼发生的方法视力下降是为了降低眼压（IOP），但这种方法是部分有效的，并不能解决问题对 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，约 10% 的青光眼患者对这些疗法没有反应。溴莫尼定是一种 α2 激动剂，滴眼剂可降低眼压并具有神经保护作用，但它会导致许多副作用，例如过敏反应和角膜疾病。与眼压一起，年龄相关的抗氧化能力下降眼组织中的氧化酶导致 RGC 和小梁网 (TM) 死亡细胞，这是现有治疗方法无法解决的问题。一氧化氮（NO）系统可能是旨在通过放松小梁网 (TM) 细胞来降低眼压来增强房水流出。在这里，我们建议开发一种强大的混合 NO 捐赠和 SOD 模拟化合物，封装在 PLGA纳米颗粒可延长降低眼压的持续时间，并具有神经保护作用。我们合成了一种新型双功能杂化化合物 SA-2，具有 NO 供体和 SOD 模拟物功能组。我们的初步结果表明，单滴 PLGA 胶囊 SA-2 纳米颗粒 (SA-2-NP) 在小鼠青光眼模型中使 IOP 降低 50%。此外，化合物 SA-2 在成年大鼠视网膜外植体的离体缺氧损伤和通过玻璃体内注射建立体内小鼠视神经挤压模型。我们的目标是 1) 优化剂量通过 SA-2-NP 的毒代动力学研究，确定在两种动物模型中降低 IOP 的功效： Ad5.TGFβ2 诱导的高眼压症 (OHTN) 小鼠模型和血压正常的猴眼。 2) 描述化合物 SA-2 保护人类 TM 的生化机制青光眼变化引起的细胞和 RGC。 3) 评估局部施用的 SA-2-NP 的效果在两种模型中预防 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小鼠模型（慢性损伤）。顺利完成上述建议研究将提供有关 SA-2-NP 的最大有效剂量和给药频率的信息这将作为我们未来的目标在激光诱导 OHTN 猴子模型中进行进一步评估，并最终将人体临床试验取得进展。研究结果将对该领域产生重大影响开发具有降低眼压和神经保护作用的新型非前列腺素疗法影响。