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: 8011240
• 负责人: IAN S ZAGON
• 金额: $ 19.71万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011240
• 关键词: Adhesions; Alloxan; Animal Experiments; Animal Model; Animals; Apoptosis; Biological Response Modifier Therapy; Blindness; Blood Glucose; Caliber; Cell Count; Cell Cycle; Cell Proliferation; Characteristics; Chronic Disease; Cicatrix; Clinical; Clinical Trials; Companions; Complex; Complications of Diabetes Mellitus; Cornea; Corneal Abrasion; Corneal Injury; Corneal Ulcer; DNA biosynthesis; Data; Defect; Diabetes Mellitus; Dose; Electron Microscopy; Endothelial Cells; Endothelium; Enkephalins; Epithelial; Excision; Eye; Eyedrops; Fatty acid glycerol esters; Frequencies; G1 Phase; Grant; Growth; Growth Factor; Guidelines; Healed; Health; Histology; Hyperglycemia; Incidence; Individual; Injection of therapeutic agent; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Interruption; Keratopathy; Kidney Diseases; Lesion; Limbus Corneae; Measurement; Measures; Microscopy; Modeling; Molecular and Cellular Biology; Monitor; Morbidity - disease rate; Naltrexone; Narcotic Antagonists; Necrosis; Neuropathy; Ophthalmologist; Opioid; Opioid Peptide; Opioid Receptor; Oryctolagus cuniculus; Pain; Pathogenesis; Pathway interactions; Patients; Perception; Peripheral; Phase; Phase I Clinical Trials; Physiologic Intraocular Pressure; Physiology; Plasma; Population; Rattus; Recurrence; Research; Research Ethics Committees; Residual state; Retinal Diseases; Safety; Scientist; Secure; Severities; Signal Transduction; Streptozocin; Structure; Testing; Therapeutic; Thick; Time; Topical application; Toxic effect; United States Food and Drug Administration; Vitrectomy; Wound Healing; bench to bedside; conjunctiva; corneal epithelium; cytotoxicity; design; diabetes control; diabetic; diabetic patient; diabetic rat; dosage; endogenous opioids; healing; injured; innovation; methionine-enkephalin receptor; morphometry; novel; preclinical study; prevent; receptor; subcutaneous; tonometry; type I diabetic

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)： 在50%的糖尿病患者中，发现从表面缺陷到全层上皮病变的角膜侵蚀/擦伤，这种情况被称为糖尿病角膜病变。此外，由于使用糖尿病患者的供体角膜，以及糖尿病患者在玻璃体切割术中摘除角膜上皮，导致角膜再上皮化困难和持续性上皮缺陷/反复侵蚀。这种角膜上皮缺陷会导致感染性角膜溃疡、继发性瘢痕形成和视力丧失。令人信服的证据表明，阿片类拮抗剂纳曲酮(NTX)阻断阿片-受体相互作用，可以恢复失控糖尿病患者的角膜上皮伤口愈合。这笔赠款旨在实现从板凳到床边的过渡，并探索了局部应用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。一个由一名基础科学家、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经建立了合作伙伴关系，以充分发挥这一细胞和分子生物学进步的治疗潜力。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，以了解NTX对动态平衡(未受伤)和受损的角膜上皮的毒性和有效性。为了满足FDA的要求，我们使用了两种动物：老鼠和兔子。这笔赠款利用了一个有充分证据的可靠的大鼠和兔角膜上皮化模型，通过注射链脲佐菌素(STZ)(大鼠)或四氧嘧啶(兔)诱导1型糖尿病，以及皮下胰岛素颗粒来维持正常血糖。R21研究了NTX对大鼠未损伤(特异靶1)和损伤(特异靶2)角膜上皮以及未损伤兔角膜上皮(特异靶3)的影响。R33研究了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。这些数据将被用来确保IND编号，以便进行临床试验，并作为机构审查委员会批准进行第一阶段临床试验的证据。 建议使用NTX进行生物治疗是一种创新的方法，通过操纵患者自身的生长调节机制来纠正糖尿病并发症。