Optimizing Rho-associated kinase inhibitors for use in treating Fuchs endothelial corneal dystrophy

优化 Rho 相关激酶抑制剂用于治疗福克斯内皮性角膜营养不良

基本信息

批准号：
10684764
负责人：
Mark Aaron Greiner
金额：
$ 19.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684764
关键词：
Acceleration Adjuvant Therapy Adverse effects Affect Age Years American Attention Autopsy Biochemical Blindness Case Series Cell Adhesion Cell Culture Techniques Cell Cycle Progression Cell Death Cell Density Cell physiology Cells Cellular Morphology Clinical Clinical Trials Clinical assessments Conjunctivitis Cornea Corneal Endothelium Corneal edema Data Defect Deposition Development Diagnosis Disease Disease Progression Dose Drug Exposure Early Diagnosis Encapsulated Endothelial Cells Endothelium Epithelium Event Excision Extracellular Matrix Formulation Frequencies Fuchs&apos Endothelial Dystrophy Functional disorder Future Growth Head High Prevalence Human Impairment In Vitro Investigation Keratoplasty Measures Membrane Proteins Mesenchymal Modeling Molecular Mus Mutation Operative Surgical Procedures Outcomes Research Oxidative Stress Pathogenesis Pathologic Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Phenotype Physiologic Intraocular Pressure Population Public Health Regimen Research Rewards Rho-associated kinase Safety Swelling Testing Therapeutic Thick Tissue Donors Tissue Transplantation Tissues Toxic effect Transplantation Transplantation Surgery Treatment Efficacy Work alternative treatment cell motility clinical application clinical effect clinical efficacy density disorder prevention early onset efficacy study end stage disease head-to-head comparison high risk innovation irritation kinase inhibitor mouse model nanoparticle nanoparticle delivery novel overexpression preclinical study prevent response side effect standard of care uptake wound closure wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT Fuchs endothelial corneal dystrophy (FECD) is a polygenic disease that affects 6.1 million Americans over 40 years of age and is the leading indication for corneal transplant surgery in the U.S. FECD is diagnosed based on visible damage to corneal endothelial cells (CECs) and degenerative extracellular matrix deposits on the inner cornea (guttae). FECD pathogenesis is characterized by CEC dysfunction, endothelial-to-mesenchymal transition (EMT), extracellular matrix (ECM) degeneration, and CEC death that lead to vision loss. Although it can be diagnosed early, FECD requires corneal transplantation for vision loss because there are no therapies to prevent its progression. We found previously that the Rho-associated kinase inhibitor (RKI) ripasudil decreases FECD phenotypes, warranting an exploration of its potential as a possible therapeutic option to prevent transplantation. Currently, two RKIs (netarsudil and ripasudil) are being used as adjuvant therapies to accelerate endothelial wound healing in Descemetorhexis without endothelial keratoplasty (DWEK). Studies have not yet been performed comparing these two RKIs head-to-head. Problems with RKI treatments include ocular irritation and frequent dosing requirements. Additionally, RKIs have not been tested as a preventative for FECD progression. The overall objectives of the proposed research are to determine the relative efficacy of two RKIs (netarsudil and ripasudil) for use in two distinct applications for the treatment of FECD (DWEK, primary drug therapy to prevent FECD progression). Our central hypothesis is that netarsudil and ripasudil will have equivalent efficacy in wound healing and FECD phenotype reversal, and that packaging RKIs into targeted nanoparticles (NPs) will decrease off-target side effects and permit reduced dosing frequency. The rationale for the proposed research includes the following: i) head-to-head RKI comparisons are needed because if netarsudil works then clinical use may be achieved more quickly; ii) dose-reduction and sustained-release strategies are needed because ocular irritation limits RKI use; and iii) testing RKIs for suppression of FECD phenotypes is needed to determine if future clinical trials are warranted. Guided by strong preliminary data, our hypothesis will be tested through the following specific aims: 1) Determine the optimum dosing of RKIs in a FECD DWEK treatment model; and 2) Determine the clinical efficacy and toxicity of RKIs with and without targeted NP packaging in a FECD disease prevention mouse model. The approach is innovative in its use of a new cell culture model that makes it possible to delineate the pathological events related to disease progression in early-onset FECD, as well as novel nanoparticles that are capable of delivering drugs to FECD cells with more efficiency and less toxicity. The proposed research is significant because RKI use would permit FECD treatment alternatives that do not rely on donor corneal tissue or corneal transplantation (only 1 donor cornea is available for every 70 needed worldwide). This proposal is of higher risk because it is unknown if RKIs can prevent FECD disease progression, but has a high potential reward of developing drug therapy treatments that may delay or prevent surgery.

项目概要/摘要福克斯内皮性角膜营养不良 (FECD) 是一种多基因疾病，影响了 610 万美国人 40岁，是美国角膜移植手术的主要指征。FECD是根据诊断角膜内皮细胞 (CEC) 可见损伤和内层退行性细胞外基质沉积角膜（古塔）。 FECD 发病机制的特点是 CEC 功能障碍、内皮间质转变 (EMT)、细胞外基质 (ECM) 变性和 CEC 死亡导致视力丧失。虽然它可以早期诊断，FECD 需要角膜移植来治疗视力丧失，因为没有治疗方法阻止其进展。我们之前发现 Rho 相关激酶抑制剂 (RKI) 瑞帕舒地尔可降低 FECD 表型，值得探索其作为预防的可能治疗选择的潜力移植。目前，两种 RKI（netarsudil 和 ripasudil）被用作辅助疗法，以加速不进行内皮角膜移植术 (DWEK) 的撕碎弹力术中的内皮伤口愈合。研究尚未对这两个 RKI 进行了头对头比较。 RKI 治疗的问题包括眼睛刺激和频繁的给药要求。此外，RKI 尚未经过测试作为 FECD 的预防措施进展。拟议研究的总体目标是确定两种 RKI 的相对功效（netarsudil 和 ripasudil）用于两种不同的治疗 FECD 的应用（DWEK，主要药物预防 FECD 进展的治疗）。我们的中心假设是，netarsudil 和 ripasudil 将具有等效的伤口愈合和 FECD 表型逆转的功效，以及将 RKI 包装到靶向纳米颗粒中（NP）将减少脱靶副作用并允许减少给药频率。拟议的理由研究包括以下内容： i) 需要进行头对头 RKI 比较，因为如果 netarsudil 有效，那么可以更快地实现临床应用； ii) 需要减少剂量和缓释策略因为眼部刺激限制了 RKI 的使用； iii) 需要测试 RKI 是否抑制 FECD 表型确定是否有必要进行未来的临床试验。在强有力的初步数据的指导下，我们的假设将得到检验通过以下具体目标： 1) 确定 FECD DWEK 治疗模型中 RKI 的最佳剂量； 2) 确定 FECD 中带或不带靶向 NP 包装的 RKI 的临床疗效和毒性疾病预防小鼠模型。该方法的创新之处在于它使用了一种新的细胞培养模型，使得可以描述早发性 FECD 中与疾病进展相关的病理事件，以及新型纳米颗粒能够以更高的效率和更低的毒性将药物递送至 FECD 细胞。这拟议的研究意义重大，因为 RKI 的使用将允许 FECD 治疗替代方案不依赖于供体角膜组织或角膜移植（全球每 70 名患者只能获得 1 个供体角膜）。该提议风险较高，因为尚不清楚 RKI 是否可以预防 FECD 疾病进展，但有一个开发可能延迟或阻止手术的药物治疗具有很高的潜在回报。