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

• 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
• 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

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，估计患病率为8000万 到2020年，全球至少有600万至800万人双目失明。高眼压(IOP) 导致视神经轴突变性和视网膜神经节细胞进行性丢失 这些都是青光眼的特征。临床上，减缓青光眼的唯一方法 视力丧失是为了降低眼压，这是部分有效的，但不能解决 对RGC变性的易感性。目前青光眼的治疗方法包括使用前列腺素类似物 然而，基于降眼压药物，大约10%的青光眼患者对这些治疗没有反应。 布里莫尼定是一种α2激动剂，滴眼液可降低眼压，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。伴随着眼压，与年龄相关的抗- 眼组织中的氧化酶导致视网膜神经节细胞和小梁细胞的死亡(TM) 细胞，这是可用的治疗方法没有解决的问题。一氧化氮(NO)系统可能是 旨在通过松弛小梁网络(TM)细胞以降低眼压来增强房水流出。 在这里，我们建议开发一种健壮的杂交NO供体和SOD模拟化合物，封装在 PLGA纳米粒可延长降眼压持续时间，并具有神经保护作用。 我们合成了一种新型的无供体和超氧化物歧化酶模拟物的双功能杂化化合物SA-2 功能基团。我们的初步结果表明，一滴PLGA滴眼液包埋了 SA-2纳米粒(SA-2-NPs)在小鼠青光眼模型中降低了50%的眼压。另外， 化合物SA-2对成年大鼠视网膜外植体体外低氧损伤和体外缺氧损伤均具有高度的神经保护作用。 玻璃体内注射法制备小鼠视神经卡压模型。我们的目标是1)优化剂量 通过SA-2-NPs的毒代动力学研究，并确定其对两种动物模型的降眼压效果：A Ad5、转化生长因子β2诱导的高眼压小鼠模型及正常血压猴眼模型。 2)阐明化合物SA-2保护人TM的生化机制 青光眼改变所致的细胞和视网膜节细胞。3)评估局部给药的SA-2-NPs 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(慢性损伤)小鼠模型。圆满完成上述建议 研究将提供有关SA-2-NPs的最大有效剂量和剂量频率的信息 这将在激光诱导的OHTN猴子模型中进一步评估，作为我们未来的目标，并最终将 人类临床试验的进展。这一结果将对该领域产生重大影响，并对 开发兼具降眼压和神经保护作用的新型非前列腺素类药物 效果。