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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：
10226000
负责人：
Suchismita Acharya
金额：
$ 35.81万
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/10226000
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