Prevention of Retinopathy of Prematurity with a Novel Bifunctional Redox Reagent

用新型双功能氧化还原试剂预防早产儿视网膜病变

• 批准号: 8051014
• 负责人: Kanneganti Murthy
• 金额: $ 22.06万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051014
• 关键词: 3-nitrotyrosine; Accounting; Address; Air; American; Animal Model; Antioxidants; Arginine; Attenuated; Biological; Birth; Blindness; Blood Vessels; Canis familiaris; Clinical; Clinical Treatment; Clinical Trials; Complication; Diffusion; Dose; Drug Delivery Systems; Enzymes; Euthanasia; Evaluation; Excision; Exposure to; Free Radicals; Functional disorder; Gold; High Prevalence; Hydrogen Peroxide; Hyperoxia; Infant; Inflammation; Injury; Ischemia; Laboratories; Lipid Peroxidation; Low Birth Weight Infant; Measures; Medical; Microcirculation; Mission; Mitochondria; Modeling; Mus; NADPH Oxidase; Neonatal; Newborn Infant; Nitric Oxide; Nitrogen; Orphan Drugs; Oxidation-Reduction; Oxygen; Peroxonitrite; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Placebo Control; Poly Adenosine Diphosphate Ribose; Polyunsaturated Fatty Acids; Population; Premature Infant; Prevention; Production; Prophylactic treatment; Protocols documentation; Randomized; Rattus; Reaction; Reactive Oxygen Species; Reagent; Relative (related person); Retina; Retinal; Retinopathy of Prematurity; Rodent Model; Safety; Series; Small Business Innovation Research Grant; Superoxide Dismutase; Superoxides; Technology; Testing; Therapeutic; Thioctic Acid; Tissues; Toxicology; Translating; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vision; Visual Acuity; Visual impairment; arginase; base; catalase; catalyst; clinically relevant; human NOS3 protein; innovation; intraperitoneal; medical schools; meetings; mimetics; neovascularization; novel; overexpression; premature; prevent; prophylactic; prospective; pup; response; retina blood vessel structure; retinal ischemia; small molecule; treatment effect; vasoconstriction

DESCRIPTION (provided by applicant): Retinopathy of prematurity (ROP) is present in up to 70-85% of very low birthweight premature infants (< 1 kg). The more severe forms of ROP (Grades 3-5) account for more than 50% of injuries and are associated with lifelong visual impairment, including blindness. There are no pharmaceutical agents, or other measures, approved for the prevention of ROP. An effective prophylaxis of ROP would preserve vision and transform medical management of prematurity. ROP results from the abrupt increase in oxygenation at birth that produces a relative hyperoxia in the premature retina, resulting in the excessive production of superoxide anion. Hyperoxia also induces arginase-1 overexpression, which depletes L-arginine, the precursor of the endothelial nitric oxide (NO) synthase (ecNOS), thereby blocking NO synthesis and diverting the uncoupled ecNOS to synthesize superoxide. Compounding this increase in superoxide production is the ontogenic deficiency of anti-oxidant enzymes, such as superoxide dismutase. The resulting relative abundance of retinal superoxide and paucity of NO create an imbalance of these two free radical species that vasoconstricts the retinal microcirculation and induces retinal ischemia. The response to ischemia futher triggers aberrant production of vascular endothelial growth factor (VEGF), which in turn stimulates neoproliferation of retinal blood vessels. The ensuing retinal avascularity (RA) and intravitreous neovascularization (IVNV) contribute to significant visual impairment. A successful prophylactic of ROP requires the simultaneous replenishment of NO and removal of superoxide. To meet this unmet need, we are developing R-200, a novel agent formed from 2 redox-based moieties: 1) an organic nitrovasodilator moiety that releases NO, and 2) a lipoic acid moiety that acts as an SOD mimetic, a catalase mimic that detoxifies hydrogen peroxide, and a peroxynitrite decomposition catalyst. Taken together, R-200 removes superoxide and delivers NO without the confounding effect of peroxynitrite formation. Specific Aim: Establish the efficacy of R-200 in a clinically-relevant neonatal murine model of ROP. We will carry out a dose-response study of retinal injury induced in mouse pups exposed to 70% O2 for 7 days, followed by room air for 10 days. Prophylactic administration of R-200 will be initiated at the onset of hyperoxic exposure. We expect that R-200 will: 1) attenuate morphologic injury, as manifested reductions in retinal flat-plate evaluation for RA and IVNV, and 2) reduce retinal inflammation and injury, as manifested by reductions in retinal lipid peroxidation, VEGF concentration, and formation of peroxynitrite and poly(ADP-ribose). These treatment effects are expected to translate into clinical improvement, as reflected by a decrease in RA and IVNV and an increase in visual acuity. PUBLIC HEALTH RELEVANCE: Retinopathy of prematurity is a major complication in the very low birthweight infant and contributes to the high prevalence of visual impairment in this population. At present, there are no approved therapies. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant animal model.

描述（由申请人提供）： 高达 70-85% 的极低出生体重早产儿（< 1 kg）患有早产儿视网膜病变 (ROP)。较严重的 ROP（3-5 级）占受伤总数的 50% 以上，并与终生视力障碍（包括失明）相关。目前还没有批准用于预防 ROP 的药剂或其他措施。有效预防 ROP 将保留视力并改变早产儿的医疗管理。 ROP是由于出生时氧合突然增加导致早产儿视网膜相对高氧，导致超氧阴离子过量产生的结果。高氧还会诱导精氨酸酶-1 过度表达，从而耗尽内皮一氧化氮 (NO) 合酶 (ecNOS) 的前体 L-精氨酸，从而阻断 NO 合成并将未偶联的 ecNOS 转向合成超氧化物。抗氧化酶（例如超氧化物歧化酶）的个体缺陷使超氧化物产生的增加更加复杂。由此产生的视网膜超氧化物的相对丰富和一氧化氮的缺乏造成这两种自由基的不平衡，从而收缩视网膜微循环并诱发视网膜缺血。对缺血的反应进一步引发血管内皮生长因子（VEGF）的异常产生，进而刺激视网膜血管的新增殖。随后的视网膜无血管（RA）和玻璃体内新生血管（IVNV）导致严重的视力障碍。成功预防 ROP 需要同时补充 NO 和去除超氧化物。为了满足这一未满足的需求，我们正在开发 R-200，这是一种由 2 个基于氧化还原的部分组成的新型药物：1) 释放 NO 的有机硝基血管舒张剂部分，2) 充当 SOD 模拟物（过氧化氢酶）的硫辛酸部分模拟过氧化氢解毒和过氧亚硝酸盐分解催化剂。总而言之，R-200 可以去除超氧化物并释放 NO，而不会产生过氧亚硝酸盐形成的混杂效应。具体目标：确定 R-200 在临床相关的 ROP 新生儿小鼠模型中的功效。我们将对暴露于 70% O2 7 天，然后暴露于室内空气 10 天的幼鼠诱发的视网膜损伤进行剂量反应研究。 R-200 的预防性给药将在高氧暴露开始时开始。我们预计 R-200 将：1) 减轻形态损伤，表现为 RA 和 IVNV 的视网膜平板评估减少，2) 减少视网膜炎症和损伤，表现为视网膜脂质过氧化、VEGF 浓度和过氧亚硝酸盐和聚（ADP-核糖）的形成。这些治疗效果预计将转化为临床改善，如 RA 和 IVNV 的减少以及视力的提高所反映。 公共卫生相关性： 早产儿视网膜病变是极低出生体重婴儿的主要并发症，导致该人群视力障碍的高患病率。目前，还没有批准的治疗方法。我们正在开发一种针对这种情况的基本机制的新药，并将在临床相关的动物模型中测试该药物。