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.

项目摘要 色素性视网膜炎（RP）是一组遗传疾病，其中一个在其中一个中的多个不同突变之一 超过50个基因会导致杆感光细胞死亡。消除了大多数杆后， 锥形感受器的死亡发生，导致视野的等级丧失，可能导致失明。那里 目前，RP的治疗选择很少，并且锥细胞死亡的机理一直是受试者 激烈的研究。我们和其他人已经确定氧化和亚硝化损害是进行性损失的关键 锥光受体。我们证明了Metipranolol，一种非选择性的β-肾上腺素受体拮抗剂 口服用于治疗动脉高血压，并局部用于降低眼内压（IOP） 减少亚硝化应激，并促进RD RD小鼠模型中的锥生存和功能。 重要的是，局部给药3倍/天比每天都更有效地保留剩余功能 皮下注射。但是，用常规的眼部滴来向视网膜输送毒品要容易得多 在小鼠中比在大眼睛中，此外，患者通常不遵守需要多种剂量的药给药方案 每天剂量。为此，我们发现了一种有效地向视网膜运送药物的方法 大型动物，包括兔子和猪，每天都有局部眼部滴。我们独特的基于眼滴的药物 递送技术可改善水固体和缺水药物的眼内输送， 例如甲状腺素。我们假设一种新的低音胶合眼滴配方，旨在最大化 停留时间，眼内穿透和药物递送到视网膜的毒性最小将是 朝着开发新的RP和其他永久退化的新的每日治疗的重要一步 疾病。有了Metipranolol在人类中建立的眼部安全性和耐受性，它是理想的候选人 开发出首先的眼睛下降，以保留RP的视觉。在特定目标1中，我们将发展并完全 表征新的聚合物混合物的最佳粘度，剪切稀疏，扩散，凝胶速率和眼内 Metipranolol的渗透。在特定目标2中，我们将测试针对各种键优化的胶凝公式 小鼠和RP大鼠模型中的性质与标准液体眼滴。在特定目标3中，我们将评估 猪中的眼科药代动力学被认为是人类最相关的动物模型 眼滴剂，因为眼睛的大小和结构最相似，因此与表征最相关 带有局部配方传递到视网膜。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产物的安全性 眼睛对潜在毒性的敏感性。如果这些临床前研究按预期进行，我们将 位置良好，用于转化为诊所。