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: 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
• 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' 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

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 视网膜色素变性(RP)是一组遗传性疾病，其中一种是多种不同突变之一 有50多个基因导致杆状感光细胞死亡。在大多数棒被消除后，进展 视锥感光细胞死亡，导致视野逐渐丧失，从而导致失明。那里 目前对RP的治疗选择很少，锥体细胞死亡的机制一直是研究的主题 全神贯注学习。我们和其他人已经确定氧化和亚硝基损伤是渐进性损失的关键 视锥感光器。我们证明了非选择性β肾上腺素能受体拮抗剂美替普纳洛尔 口服用于治疗动脉高压，局部用于降低眼压，也 减少亚硝化应激，促进视锥细胞存活和功能的rd10小鼠模型。 重要的是，每天3次局部用药在保护视网膜功能方面比每天用药更有效。 皮下注射。然而，用传统的眼药水将药物输送到视网膜要容易得多。 在老鼠身上，比在大眼睛里，而且，患者往往不坚持需要多次给药的方案 每天的剂量。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，每天局部滴眼液一次。我们独一无二的滴眼剂 输送技术改进了水溶和水不溶药物的眼内输送， 比如美替普纳洛尔。我们假设一种新的低渗性凝胶滴眼液配方旨在最大化 滞留时间、眼内渗透和药物以最小的毒性输送到视网膜将是一个 朝着开发一种新的每日一次的治疗RP和其他视网膜退行性变的重要步骤 精神错乱。鉴于美替普纳洛尔在人体内已经确立的眼部安全性和耐受性，它是治疗以下疾病的理想候选药物 开发一种首创的用于保护RP视力的眼药水。在具体目标1中，我们将发展和充分 描述新型聚合物混合物的最佳粘度、剪切变稀、铺展、凝胶率和眼内情况 美替普纳洛尔的透皮吸收。在具体目标2中，我们将测试针对各种关键因素进行优化的凝胶配方 小鼠和大鼠RP模型与标准液体滴眼液的比较。在具体目标3中，我们将评估 猪的眼部药代动力学，这被认为是与人类最相关的局部用药动物模型 滴眼液剂量，因为眼睛的大小和结构最相似，因此与特征最相关 通过外用配方向视网膜输送。我们将进一步评估兔眼的生物相容性， 由于眼睛结构的相似性，最常用的动物模型来评估眼科产品的安全性 以及眼睛对潜在毒性的敏感性。如果这些临床前研究如预期那样取得进展，我们将 已经做好了移植到诊所的准备。

项目成果

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.

• DOI: 10.1016/j.freeradbiomed.2022.01.032
• 发表时间: 2022-03
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Kanan Y;Hackett SF;Taneja K;Khan M;Campochiaro PA
• 通讯作者: Campochiaro PA