Naltrexone as a Novel Treatment for Diabetic Keratopathy

纳曲酮作为糖尿病角膜病的新型治疗方法

• 批准号: 7287707
• 负责人: IAN S ZAGON
• 金额: $ 37.23万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287707
• 关键词: Alloxan; Animal Experiments; Animal Model; Animals; Biological Response Modifier Therapy; Blindness; Cicatrix; Clinical Trials; Complications of Diabetes Mellitus; Condition; Cornea; Corneal Abrasion; Corneal Ulcer; Data; Defect; Diabetes Mellitus; Dose; Epithelial; Excision; Grant; Growth; Guidelines; Individual; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Keratopathy; Lesion; Modeling; Molecular and Cellular Biology; Naltrexone; Narcotic Antagonists; Numbers; Ophthalmologist; Opioid Receptor; Oryctolagus cuniculus; Patients; Phase; Phase I Clinical Trials; Range; Rattus; Recurrence; Research; Research Ethics Committees; Safety; Scientist; Secure; Streptozocin; Testing; Therapeutic; Thick; Topical application; Toxic effect; United States Food and Drug Administration; Vitrectomy; Wound Healing; bench to bedside; corneal epithelium; design; diabetic; injured; innovation; novel; prevent; subcutaneous

DESCRIPTION (provided by applicant): Corneal erosions/abrasions ranging from superficial defects to full thickness epithelial lesions are found in 50% of diabetic patients, and this condition is termed diabetic keratopathy. Moreover, difficulty with corneal re-epithelialization and persistent epithelial defects/recurrent erosions is associated with the use of donor corneas from diabetic patients, and with corneal epithelial removal during vitrectomy in diabetic individuals. Such corneal epithelial defects can result in infectious corneal ulcers, secondary scarring, and loss of vision. Compelling evidence shows that blockade of opioid-receptor interactions by the opioid antagonist, naltrexone (NTX), restores corneal epithelial wound healing in uncontrolled diabetes. This grant is designed to make the transition from bench to bedside and explores the hypothesis that topical application of NTX will prevent and/or ameliorate corneal epithelial wound healing complications related to Type 1 diabetes. A multi-disciplinary research team consisting of a basic scientist, two ophthalmologists, and a biostatistician have formed a partnership in order to reach the full therapeutic potential of this advance in cell and molecular biology. In the R21 phase (with completion in the R33 phase), this hypothesis is tested in animal models of well-controlled Type 1 diabetes as to the toxicity and efficacy of NTX in the homeostatic (unwounded) and injured corneal epithelium. In order to prepare for FDA requirements, two species of animals are utilized: rat and rabbit. The grant utilizes a well-documented and reliable model of corneal re-epithelialization in the rat and rabbit, induction of Type 1 diabetes by injection of streptozotocin (STZ) (rats) or alloxan (rabbits), and subcutaneous insulin pellets to maintain normoglycemia. The R21 studies the effects of NTX on uninjured (Specific Aim #1) and injured (Specific Aim #2) corneal epithelium of rats, and the uninjured rabbit corneal epithelium (Specific Aim #3). The R33 investigates the safety and efficacy of NTX treatment in corneal abrasions in the diabetic rabbit (Specific Aim #1). If the animal experiments successfully show a non-toxic dose with efficacy, we will perform due diligence testing under the guidelines of the Food and Drug Administration (Specific Aim #2). These data will be used to secure an IND number in order to pursue clinical trials, and as evidence for Institutional Review Board approval to conduct Phase I clinical trials. The proposed use of biotherapy with NTX is an innovative approach whereby the patient's own growth regulatory mechanisms are manipulated to correct complications from diabetes.

描述（由申请人提供）： 50%的糖尿病患者会出现从浅表缺损到全层上皮损伤的角膜糜烂/擦伤，这种情况被称为糖尿病性角膜病变。此外，角膜上皮再形成困难和持续性上皮缺陷/反复糜烂与使用糖尿病患者的供体角膜以及糖尿病个体玻璃体切除术期间角膜上皮的去除有关。这种角膜上皮缺陷可导致感染性角膜溃疡、继发性疤痕和视力丧失。令人信服的证据表明，通过阿片拮抗剂纳曲酮（NTX）阻断阿片受体相互作用，可以恢复不受控制的糖尿病的角膜上皮伤口愈合。这笔资助旨在实现从实验室到临床的转变，并探索局部应用 NTX 将预防和/或改善与 1 型糖尿病相关的角膜上皮伤口愈合并发症的假设。由一名基础科学家、两名眼科医生和一名生物统计学家组成的多学科研究团队已建立合作伙伴关系，以充分发挥细胞和分子生物学这一进展的治疗潜力。在 R21 阶段（在 R33 阶段完成），这一假设在控制良好的 1 型糖尿病动物模型中进行了测试，以确定 NTX 在稳态（未受伤）和受伤角膜上皮中的毒性和功效。为了满足 FDA 的要求，使用了两种动物：大鼠和兔子。该拨款利用了大鼠和兔子角膜再上皮化的有据可查且可靠的模型，通过注射链脲佐菌素 (STZ)（大鼠）或四氧嘧啶（兔子）诱导 1 型糖尿病，以及皮下注射胰岛素颗粒以维持正常血糖。 R21 研究 NTX 对未受伤（特定目标 #1）和受伤（特定目标 #2）的大鼠角膜上皮以及未受伤的兔子角膜上皮（特定目标 #3）的影响。 R33 研究 NTX 治疗糖尿病兔角膜擦伤的安全性和有效性（具体目标 #1）。如果动物实验成功证明无毒剂量有效，我们将根据美国食品和药物管理局的指导方针（具体目标#2）进行尽职调查测试。这些数据将用于获得 IND 编号以进行临床试验，并作为机构审查委员会批准进行 I 期临床试验的证据。 拟议使用 NTX 生物疗法是一种创新方法，通过操纵患者自身的生长调节机制来纠正糖尿病并发症。