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

• 批准号: 10326840
• 负责人: Peter A Campochiaro
• 金额: $ 39.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10326840
• 关键词: Adrenergic Antagonists; Animal Model; Animals; Biological; Blindness; Blinking; Bruch' 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; base; 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; safety assessment

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。大部分杆被消除后，渐进 视锥细胞死亡，导致视野逐渐丧失，从而导致失明。那里 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 的紧张学习。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 锥体感光器。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 皮下注射。然而，使用传统滴眼剂更容易将药物输送到视网膜 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 每天剂量。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，每日一次局部滴眼液。我们独特的滴眼剂药物 递送技术改善了水溶性和水不溶性药物的眼内递送， 如美替洛尔。我们假设一种新的低渗凝胶滴眼剂配方旨在最大限度地提高 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 失调。由于美替洛尔在人类中已确立的眼部安全性和耐受性，因此它是以下药物的理想候选者： 开发首创的用于保护 RP 患者视力的滴眼剂。在具体目标 1 中，我们将发展并充分 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 美替洛尔的渗透。在具体目标 2 中，我们将测试针对各种关键优化的胶凝配方 与标准液体滴眼剂在 RP 小鼠和大鼠模型中的特性比较。在具体目标 3 中，我们将评估 猪的眼部药代动力学，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 通过局部制剂递送至视网膜。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取得进展，我们将 非常适合转化为临床。