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：
10477236
负责人：
Suchismita Acharya
金额：
$ 35.89万
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/10477236
关键词：
3-nitrotyrosine Address Adult Affect African Green Monkey Aftercare Allergic Reaction Animal Model Anterior Antioxidants Apoptotic Aqueous Humor Bilateral 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 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 Persons 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 delivery vehicle 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.

青光眼是眼睛的神经退行性疾病，估计患者的患病率估计到2020年，全球至少有6至800万个双侧盲。升高的眼压（IOP）引起视神经的轴突变性和残留神经节细胞的逐渐丧失（RGC）这是青光眼的特征标志。在临床上，减缓青光眼的唯一方法视力丧失是为了减少眼内压（IOP），这是部分有效的，并且无法解决 RGC变性的敏感性。目前的青光眼疗法包括使用前列腺素类似物但是，基于降低剂的IOP剂，约有10％的青光眼患者对这些疗法没有反应。 brimonidine，一种α2激动剂，眼睛吸收降低IOP，也是神经保护性的，但是它会导致许多副作用，例如过敏反应和角膜疾病。与IOP一起，抗年龄相关的抗年龄下降眼组织中的氧化剂酶有助于RGC和小梁网（TM）死亡细胞，该细胞无法通过可用的治疗方法来解决。一氧化氮（NO）系统可能是通过放松小梁网（TM）细胞以降低IOP来增强水出口。在这里，我们建议开发出强大的混合杂种无捐赠和模拟物种封装在 PLGA纳米颗粒将延长降低IOP的持续时间并具有神经保护作用。我们已经合成了一种新型的双功能混合化合物SA-2，没有供体和SOD模拟官能团。我们的初步结果表明，一滴PLGA已封装在小鼠青光眼模型中，SA-2纳米颗粒（SA-2-NP）降低了IOP 50％。此外，化合物SA-2在对成年大鼠永久性外植体的离体低氧侮辱中都具有高度神经保护作用体内小鼠视神经挤压模型通过玻璃体内注射。我们的目标是1）优化剂量通过SA-2-NP的有毒动力学研究，并确定在两个动物模型中降低IOP的效率：A 由AD5.TGFβ2诱导的眼部高血压（OHTN）的小鼠模型和正常的猴子眼。 2）描述复合SA-2的生化机制青光眼变化的细胞和RGC。 3）评估其额外管理的SA-2-NP 在两种模型中预防RGC死亡的能力：视神经压伤的小鼠模型（创伤性损伤）和A 小鼠高血压的模型（慢性损伤）。成功完成上述提议研究将提供有关SA-2-NP的最大有效剂量和剂量频率的信息这将在激光引起的OHTN猴子模型中进一步评估，这是我们的未来目标，最终将进展到人类临床试验。结果将对现场产生重大影响，对开发具有IOP降低和神经保护性的新型非prostaglandin理论效果。