Co-Delivery Dose-Controllable Implants for Advanced Chronic Eye Disease Treatment

用于治疗晚期慢性眼病的共同给药剂量可控植入物

• 批准号: 10647078
• 负责人: Yoonjee Park
• 金额: $ 8.01万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647078
• 关键词: Absorbable Implants; Adrenal Cortex Hormones; Affect; Age; Anti-Inflammatory Agents; Blindness; Bolus Infusion; Cataract; Cells; Choroidal Neovascularization; Chronic; Chronic Care; Chronic Disease; Clinical Trials; Combined Modality Therapy; Conjunctival Hemorrhage; Crystalline Lens; Data; Development; Dexamethasone; Diabetic Retinopathy; Disease; Disease Progression; Dose; Drug Controls; Drug Delivery Systems; Drug Implants; Edema; Endothelial Cells; Equipment; Extravasation; Eye; Eye diseases; Fibrosis; Frequencies; Future; Genes; Glaucoma; Glucocorticoids; Goals; Human; Implant; In Vitro; Inflammation; Inflammatory; Injections; Kinetics; Lasers; Light; Liposomes; Macular degeneration; Methods; Modeling; Monoclonal Antibodies; Nanoporous; Oryctolagus cuniculus; Outcome; Pathologic; Patients; Permeability; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Posterior Uveitis; Probability; Process; Research; Research Personnel; Retina; Retinal Vein Occlusion; Risk; Running; Structure; System; Technology; Testing; Time; Tissues; Trabecular meshwork structure; Translational Research; Treatment Efficacy; VEGF165; Vascular Endothelial Growth Factors; bevacizumab; biodegradable polymer; capsule; clinically relevant; design; diabetic; differential expression; dosage; drug release kinetics; efficacy evaluation; high intraocular pressure; histological studies; implant design; improved; in vivo; in vivo fluorescence imaging; intravitreal injection; irradiation; macular edema; novel; novel therapeutics; ranibizumab; retina blood vessel structure; side effect; standard of care; transcriptome sequencing; translational scientist

PROJECT SUMMARY/ABSTRACT Chronic posterior eye diseases, such as diabetic macular edema (DME), macular edema (ME) caused by retinal vein occlusion, wet age-released macular degeneration (wet AMD) and non-infectious posterior uveitis (NU), are associated with high rates irreversible vision loss. Current standard of care for DME, ME and wet AMD is monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) monoclonal antibody, Bevacizumab (Bev), or the fragment, Ranibizumab (Ran). In addition, because those diseases are characterized by inflammation and fibrosis, intravitreal corticosteroid implant injections every 2~6 months is the mainstay to treat DME, ME, and NU. Recently, combination therapy of intravitreal anti-VEGF and corticosteroid implant (Ozurdex) injections has been extensively studied in clinical trials to expect better therapeutic efficacy in those chronic diseases. However, multiple frequent intravitreal injections are not only invasive and inconvenient for patients but also increase the risk of complications, such as conjunctival hemorrhage, and increased intraocular pressure (IOP). Especially, the intravitreal corticosteroid treatment causes serious local side effects, such as cataract and abnormally high IOP which can lead to glaucoma. Because the peak IOP is highly associated with the drug (dexamethasone, Dex) concentration in the vitreous/retina released from Ozurdex, we hypothesize that the local side effect is due to the inability to adjust dosage and burst release characterized by high concentration in shorter time than desired. The central hypothesis of this proposal is that our novel dose-controllable co-delivery implant of Dex/Ran would reduce the side effects due to uncontrollable dosage after intravitreal administration, and extend therapeutic efficacy. We recently developed a biodegradable light-activated implant that can be intravitreally injected and triggered by laser through the lens of the eye for dose-controlled drug release safely. The drug dosage can be precisely and easily controlled by varying laser parameters, such as power and duration. The overall goal of this research is to improve the treatment of chronic posterior eye diseases and reduce side effects caused by current corticosteroid treatment methods by developing a dose-controllable co-delivery drug implant. The focus of Aim 1 is to complete the development of a dose-controllable co-delivery Dex/Ran implant and investigate the drug release kinetics in vitro. Aim 2 focuses on defining effect of different drug delivery methods on reducing side effects, glaucoma, utilizing human trabecular meshwork cells. Aim 3 will determine in vivo efficacy and reduced side effects of the implant compared to the traditional methods, i.e. Ozurdex and monthly Ran injections, in a retinal vessel leakage/edema rabbit model. At the successful completion of this project, expected outcomes include identifying feasibility of the dose-controllable implants to potentially change the standard of care for chronic posterior eye drug delivery. In addition, the project will support future R01 application by generating preliminary data and enhance the PI to be an independent researcher in the field of translational science.

项目总结/摘要 慢性后眼部疾病，如糖尿病性黄斑水肿（DME）、由糖尿病性黄斑水肿（ME）引起的黄斑水肿（DME）、糖尿病性黄斑水肿（ME）、糖尿病 视网膜静脉阻塞、湿性年龄释放性黄斑变性（湿性AMD）和非感染性后葡萄膜炎 (NU)与高比率的不可逆视力丧失相关。DME、ME和湿的当前治疗标准 AMD是每月玻璃体内注射抗血管内皮生长因子（VEGF）单克隆抗体， 贝伐单抗（Bev）或其片段雷珠单抗（Ran）。此外，由于这些疾病是 以炎症和纤维化为特征，每2~6个月玻璃体内注射皮质类固醇植入物是 主要治疗DME、ME和NU。近年来，玻璃体内抗VEGF和皮质类固醇的联合治疗， 在临床试验中已对植入剂（Ozurdex）注射剂进行了广泛研究，以期望获得更好的治疗效果 在这些慢性疾病中。然而，多次频繁的玻璃体内注射不仅是侵入性的， 对患者不方便，但也增加了并发症的风险，如结膜出血， 眼内压（IOP）升高。特别是玻璃体内皮质类固醇治疗， 副作用，如白内障和可导致青光眼的异常高IOP。因为眼压峰值 与玻璃体/视网膜中药物（地塞米松，Dex）浓度高度相关， Ozurdex，我们假设局部副作用是由于无法调整剂量和突释 其特征在于在比所需更短的时间内获得高浓度。这一提议的核心假设是， 我们的新型剂量可控的Dex/Ran共递送植入物将减少由于无法控制的 玻璃体内给药后的剂量，并延长治疗效果。我们最近开发了一个 可生物降解的光激活植入物，可通过透镜玻璃体内注射并由激光触发 用于剂量控制药物安全释放。药物剂量可以精确和容易地控制， 改变激光参数，例如功率和持续时间。本研究的总体目标是提高 治疗慢性眼后部疾病并减少当前皮质类固醇治疗引起的副作用 方法通过开发剂量可控的共递送药物植入物。目标1的重点是完成 开发剂量可控的共递送Dex/Ran植入物，并研究药物释放动力学， 体外目的2着重于确定不同药物递送方法对减少副作用、青光眼、 利用人类小梁细胞。目的3将确定在体内的功效和减少的副作用， 与传统方法（即Ozurdex和每月Ran注射）相比，在视网膜血管中植入 渗漏/水肿兔模型。该项目成功完成后，预期成果包括 确定剂量可控植入物潜在改变慢性前列腺炎护理标准的可行性， 眼后部药物递送。此外，该项目将通过生成初步的 数据和提高PI是一个独立的研究人员在翻译科学领域。