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.

项目摘要/摘要富克斯内皮角膜营养不良（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标关于角膜内皮细胞（CEC）的可见损害，并在内部造成退化性细胞外基质沉积物角膜（Guttae）。 FECD发病机理的特征是CEC功能障碍，内皮到间质的。过渡（EMT），细胞外基质（ECM）变性和CEC死亡，导致视力丧失。虽然是可以提早诊断出来，FECD需要角膜移植以进行视力丧失，因为没有疗法防止其进展。我们先前发现与Rho相关的激酶抑制剂（RKI）ripasudil降低 FECD表型，保证探索其潜力作为防止治疗选择的潜力移植。目前，两个RKI（Netarsudil和Ripasudil）被用作加速辅助疗法无内皮角膜造成术（DWEK）的降落hexis中的内皮伤口愈合。研究尚未进行了比较这两个RKI的正面比较。 RKI治疗问题包括眼部刺激和频繁的给药要求。此外，RKI尚未被测试为FECD的预防措施进展。拟议研究的总体目标是确定两个RKI的相对疗效（netarsudil和ripasudil）用于两种不同的应用，用于治疗FECD（DWEK，主要药物治疗以防止FECD进展）。我们的中心假设是Netarsudil和Ripasudil将具有同等的伤口愈合和FECD表型逆转的功效，将RKI包装到靶向纳米颗粒中（NP）将降低靶向副作用，并允许减少给药频率。提议的理由研究包括以下内容：i）需要正面的RKI比较，因为如果Netarsudil起作用，则需要可以更快地实现临床使用； ii）需要减少剂量和持续释放策略因为眼部刺激限制了RKI的使用； iii）需要测试RKIS抑制FECD表型确定是否有必要进行临床试验。在强大的初步数据的指导下，我们的假设将进行检验通过以下特定目的：1）确定在FECD DWEK治疗模型中RKI的最佳剂量； 2）确定RKI的临床功效和毒性在FECD中带有和没有针对性的NP包装疾病预防小鼠模型。这种方法在使用新的细胞培养模型时具有创新性可以描述与早期发作的疾病进展有关的病理事件，以及能够将药物输送到FECD细胞的新型纳米颗粒，其效率更高，毒性较小。这拟议的研究很重要，因为RKI使用将允许不依赖的FECD治疗替代方法供体角膜组织或角膜移植（全球每70个需要1个供体角膜）。该提议具有更高的风险开发可能延迟或防止手术的药物治疗的高潜在奖励。