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.

项目概要色素性视网膜炎（RP）是一组遗传性疾病，其中一种基因的多种不同突变之一超过 50 个基因导致视杆细胞感光细胞死亡，在大多数视杆细胞被消除后，进行性死亡。视锥细胞死亡，导致视野逐渐丧失，从而导致失明。目前针对 RP 的治疗选择很少，锥细胞死亡的机制一直是研究的主题我们和其他人已经确定氧化和亚硝化损伤是渐进性损失的关键。我们证明了美替洛尔，一种非选择性β-肾上腺素能受体拮抗剂。口服用于治疗动脉高血压，局部用药可降低眼内压 (IOP)，在 RP rd10 小鼠模型中减少亚硝化应激并促进视锥细胞存活和功能。重要的是，每天 3 次局部给药在保护视网膜功能方面比每天给药更有效然而，使用传统滴眼剂将药物输送到视网膜要容易得多。在小鼠中比在大眼睛中更有效，而且，患者通常不遵守需要多次给药的给药方案为此，我们发现了一种有效地将药物输送到视网膜的方法。大型动物，包括兔子和猪，每日一次局部滴眼剂。递送技术改善了水溶性和水不溶性药物的眼内递送，例如美替洛尔，我们发现了一种新的低渗凝胶滴眼剂配方，旨在最大限度地发挥作用。停留时间、眼内渗透以及以最小毒性将药物递送至视网膜将是朝着开发每日一次治疗 RP 和其他视网膜退行性病变的新方法迈出的重要一步由于美替洛尔在人类眼部的安全性和耐受性，它是治疗疾病的理想候选药物。开发首创的用于保护 RP 视力的滴眼剂在具体目标 1 中，我们将开发并充分利用这一点。表征新型聚合物共混物的最佳粘度、剪切稀化、铺展、凝胶率和眼内在具体目标 2 中，我们将测试针对各种关键因素优化的胶凝制剂。在特定目标 3 中，我们将评估 RP 小鼠和大鼠模型中的特性与标准液体滴眼剂的比较。猪的眼药代动力学，被认为是与人类局部用药最相关的动物模型滴眼剂剂量，因为眼睛的大小和结构最相似，因此与表征最相关我们将进一步评估兔子的眼部生物相容性。由于眼睛结构的相似性，最常用的动物模型来评估眼部产品的安全性以及眼睛对潜在毒性的敏感性如果这些临床前研究按预期进展，我们将非常适合转化为临床。

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：
发表时间：
2023-03
期刊：
影响因子：
7.4
作者：
Kanan, Yogita;Hackett, Sean F;Hsueh, Henry T;Khan, Mahmood;Ensign, Laura M;Campochiaro, Peter A
通讯作者：
Campochiaro, Peter A

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

氧化应激引起色素性视网膜炎视网膜葡萄糖代谢的改变。