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A novel hypotonic gelling eye drop for topical treatment of retinal degenerative diseases

一种用于局部治疗视网膜退行性疾病的新型低渗凝胶滴眼剂

基本信息

批准号：
10549354
负责人：
Peter A Campochiaro
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549354
关键词：
Adrenergic Antagonists Animal Model Animals Biological Blindness Blinking Bruch&apos s basal membrane structure Cell Death Cellulose Cessation of life Choroid Choroidal Neovascularization Clinic Cone Cornea Cyclosporine Data Degenerative Disorder Development Dose Drug Delivery Systems Drug Kinetics Electroretinography Eye Eyedrops Family suidae Film Formulation Gel Genes Genetic Diseases Goals Histology Human Hypertension Ions Lasers Lead Liquid substance Measurement Measures Modeling Morphology Mus Mutation Nuclear Optic Nerve Injuries Oral Oryctolagus cuniculus Osmolalities Patients Penetration Pharmaceutical Preparations Photoreceptors Physiologic Intraocular Pressure Physiological Pluronics Polymers Positioning Attribute Property Rattus Refractive Indices Regimen Retina Retinal Cone Retinal Degeneration Retinal Ganglion Cells Retinal Photoreceptors Retinitis Pigmentosa Rod Rupture Safety Series Solubility Stains Structure Subcutaneous Injections Suspensions Technology Testing Therapeutic Thick Thinness Time Topical application Toxic effect Translations Tyrosine Kinase Inhibitor Viscosity Vision Visual Fields Water absorption beta-adrenergic receptor biomaterial compatibility daily functioning density design improved mouse model nitrosative stress novel novel therapeutics ocular surface preclinical study preservation prevent residence retinal rods retinal toxicity safety assessment

项目摘要

PROJECT SUMMARY Retinitis pigmentosa (RP) is a group of genetic diseases in which one of multiple different mutations in one of more than 50 genes causes rod photoreceptor cell death. After most of the rods are eliminated, progressive death of cone photoreceptors occurs, resulting in gradual loss of visual field that can result in blindness. There are currently very few therapeutic options for RP, and the mechanism of cone cell death has been the subject of intense study. We and others have identified oxidative and nitrosative damage as key in the progressive loss of cone photoreceptors. We demonstrated that metipranolol, a nonselective β-adrenergic receptor antagonist given orally for the treatment of arterial hypertension and topically for lowering intraocular pressure (IOP), also reduces nitrosative stress and promotes cone survival and function in the rd10 mouse model of RP. Importantly, topical administration 3x/day was more effective in preserving retinal function than daily subcutaneous injections. However, it is much easier to deliver drugs to the retina with conventional eye drops in mice than in larger eyes, and further, patients often do not adhere to dosing regimens requiring multiple doses each day. To this end, we have discovered an approach for effectively delivering drugs to the retina in large animals, including rabbits and pigs, with once daily topical eye drops. Our unique eye drop-based drug delivery technology provides improved intraocular delivery of both water soluble and water insoluble drugs, such as metipranolol. We hypothesize that a new hypotonic gelling eye drop formulation designed to maximize the residence time, intraocular penetration, and drug delivery to the retina with minimal toxicity will be an important step toward the development of a new once daily treatment for RP and other retinal degenerative disorders. With metipranolol’s established ocular safety and tolerability in humans, it is an ideal candidate for developing a first-of-its-kind eye drop for preserving vision in RP. In Specific Aim 1, we will develop and fully characterize new polymer blends for optimal viscosity, shear thinning, spreading, gelation rate, and intraocular penetration of metipranolol. In Specific Aim 2, we will test gelling formulations optimized for various key properties versus standard liquid eye drops in mouse and rat models of RP. In Specific Aim 3, we will evaluate ocular pharmacokinetics in pigs, which are considered the most relevant animal model to humans for topical eye drop dosing, as the eye size and structure is the most similar, and thus most relevant for characterizing delivery to the retina with a topical formulations. We will further evaluate ocular biocompatibility in rabbits, the most commonly used animal model to assess safety of ocular products due to the similarities in eye structure and the sensitivity of the eye to potential toxicity. If these preclinical studies progress as expected, we will be well-positioned for translation to the clinic.

项目总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduced inspired oxygen decreases retinal superoxide radicals and promotes cone function and survival in a model of retinitis pigmentosa.

减少吸入氧可减少视网膜超氧自由基，并促进色素性视网膜炎模型中视锥细胞的功能和存活。

DOI：
10.1016/j.freeradbiomed.2023.01.021
发表时间：
2023
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Kanan,Yogita;Hackett,SeanF;Hsueh,HenryT;Khan,Mahmood;Ensign,LauraM;Campochiaro,PeterA
通讯作者：
Campochiaro,PeterA

Oxidative stress-induced alterations in retinal glucose metabolism in Retinitis Pigmentosa.