A Novel Treatment for Keratoconus and Keratectasias using Nitro Technology

使用硝基技术治疗圆锥角膜和角膜扩张症的新方法

基本信息

批准号：
7754376
负责人：
DAVID C PAIK
金额：
$ 19.8万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7754376
关键词：
Animals Apoptosis Biological Biological Assay Biomechanics Blindness Cell Count Cells Clinical Trials Collagen Communities Confocal Microscopy Cornea Corneal Diseases Corneal Endothelium Corneal Topography Disease Dose Endothelial Cells Epidemiology Epithelial Epithelial Cells European Eye Eye Banks Eyedrops Female German population Glutaral Goals Grant Heart Valves Histology Human In Vitro Incubated Intellectual Property International Keratoconus Laboratories Laser In Situ Keratomileusis Legal patent Life Mechanics Methods Microscope Monitor Necrosis New Zealand Nitrites Nitro Compounds Operative Surgical Procedures Oryctolagus cuniculus Patients Penetration Peripheral Phase I Clinical Trials Physiologic Intraocular Pressure Procedures Property Rights Prosthesis Publishing Reaction Research Research Personnel Riboflavin Risk Safety Self Administration Simulate Skin Transplantation Skin graft Solutions Techniques Technology Temperature Testing Thick Tissues Toxic effect Translations Transplanted tissue Ultraviolet Rays Universities Work base catalyst cell growth cost crosslink cytotoxicity design implantation in vivo instrument member new technology novel public health relevance research study response success tonometry ultraviolet irradiation vision science young adult

项目摘要

DESCRIPTION (provided by applicant): A major breakthrough in the treatment of keratoconus and post-LASIK keratectasias has been realized. Recent work by the German group of Wollensak, Spoerl, and Seiler has shown that cross-linking corneal collagen through application of riboflavin and ultraviolet light (UVR) can limit progressive vision loss in keratoconus patients. Despite these successes, the UVR therapy poses attendant risks, particularly related to ultraviolet irradiation. As such, FDA approval for clinical trials in the US has only recently been granted. The thrust of this application is to develop an alternative method of corneal collagen cross-linking using novel technology. Our recent studies indicate that collagen cross-linking through reactions with nitrite and related agents can induce corneal changes commensurate with UVR therapy. In addition, published toxicity/mutagenicity studies suggest a good safety profile for these agents. Thus, nitro technology could be used as an "eye drop alternative" to UVR treatment. Potential advantages over current UVR therapy include the omission of ultraviolet light exposure, the ability to treat thin corneas, less patient discomfort, ease of self- administration, a dose-response effect, and the ability to treat the peripheral cornea. This project is designed to lay groundwork for rapid translation of this technology into a treatment. Specifically, we will: 1. Determine an effective way to cross-link the cornea using nitro technology under conditions simulating the human cornea (i.e. pH 7.4 and 34oC). Fresh rabbit and human eye bank corneas will be incubated under a variety of conditions that include 1. nitrite with catalysts and 2. alternative nitrite related agents. The assay of thermal shrinkage temperature will be used to determine cross-linking efficacy. Stiffness changes induced will be studied using a biaxial material tester. Specific aim 1 is designed to identify one or more "candidate eye drops" that will then be used for in vivo rabbit experiments. 2. Test the hypothesis that corneal cross-linking through nitro technology is tolerated by corneal cells. Primary cultures of rabbit endothelial cells, keratocytes, and epithelial cells will be grown in vitro. The cells will then be exposed to nitro compounds found to be efficacious for cross-linking. Cytotoxicity will be evaluated using standard apoptosis and necrosis assays. The results from this aim will establish the in vitro toxicity level of nitro compounds to corneal cells. Specific aim 3. Test the hypothesis that corneal cross-linking through nitro technology has efficacy and is safe for the living eye. 33 young adult female New Zealand white rabbits will undergo daily application (for 1-6wks) of the topical nitro solution to the right eye with the fellow eye serving as a control. The animals will undergo serial examinations using 3 non-invasive instruments, a corneal topographer, in vivo confocal microscope, and applanation tonometer. Post-mortem, biomechanical strength testing, histology, and SEM will be performed. The results of this aim will establish the in vivo efficacy and safety of this technology and will dictate the feasibility of a human phase I trial. PUBLIC HEALTH RELEVANCE This research aims to develop a simple, new treatment for diseases of corneal destabilization which include keratoconus and post-surgical keratectasias. The latter conditions are devastating, long-term (5-10 years) complications following LASIK procedures. They were previously unpredicted and are currently of unknown epidemiologic proportion.

描述（由申请人提供）：已经实现了圆锥角膜和lasik肾上腺切开胸骨的重大突破。德国沃伦萨克（Wollensak），斯波尔（Spoerl）和塞勒（Seiler）的最新工作表明，通过涂抹核黄素和紫外线（UVR）通过涂抹角膜胶原蛋白（UVR）可以限制角膜可核患者的渐进视力丧失。尽管取得了这些成功，但UVR疗法仍带来随之而来的风险，尤其是与紫外线辐射有关的风险。因此，最近才批准了美国FDA批准用于美国的临床试验。该应用的目的是使用新技术开发一种角膜胶原交联的替代方法。我们最近的研究表明，通过与亚硝酸盐和相关剂的反应进行胶原蛋白交联可以诱导与UVR疗法相称的角膜变化。此外，已发表的毒性/诱变性研究表明，这些药物具有良好的安全性。因此，硝基技术可以用作UVR治疗的“眼滴替代品”。与当前UVR疗法相比，潜在的优势包括省略紫外线光暴露，治疗瘦角膜的能力，较少的患者不适，自我给药的易感性，剂量反应效应以及治疗周围角膜的能力。该项目旨在为将该技术的快速转换为一种治疗奠定基础。具体来说，我们将：1。在模拟人角膜的条件下，使用硝基技术确定一种有效的方法（即pH 7.4和34oC）。新鲜的兔子和人眼库角膜将在包括1.亚硝酸盐的催化剂和2个替代亚硝酸盐相关剂的各种条件下孵育。热收缩温度的测定将用于确定交联功效。将使用双轴材料测试仪研究引起的刚度变化。特定的目标1旨在识别一个或多个“候选眼滴”，然后将其用于体内兔实验。 2。检验以下假设：角膜细胞可以耐受硝基技术的角膜交联。兔内皮细胞，角膜细胞和上皮细胞的一级培养将在体外生长。然后，细胞将暴露于发现有效交联的硝基化合物。将使用标准凋亡和坏死测定法评估细胞毒性。该目标的结果将建立硝基化合物对角膜细胞的体外毒性水平。特定目的3。检验以下假设：通过硝基技术通过硝基技术进行角膜交联具有功效，并且对生命眼睛是安全的。 33名新西兰年轻雌性白兔子将使用局部硝基溶液（1-6wks）的右眼每天使用（1-6wks），并用作控制。这些动物将使用3种非侵入性仪器，角膜地形学家，体内共聚焦显微镜和Applanation Tonometer进行连续检查。验尸，生物力学强度测试，组织学和SEM将进行。该目标的结果将确定该技术的体内功效和安全性，并决定人类I期试验的可行性。公共卫生相关性这项研究旨在开发一种简单的新方法，以解决角膜破坏疾病，包括角膜稳定和手术后角膜肌。后一种条件是毁灭性的，长期（5 - 10年）在LASIK程序之后并发症。它们以前是未预测的，目前是流行病学的未知比例。