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）： 早产儿视网膜病变（ROP）存在于高达70-85%的极低出生体重早产儿（< 1 kg）中。更严重的ROP（3-5级）占受伤人数的50%以上，并与终身视力障碍有关，包括失明。没有药物制剂或其他措施被批准用于预防ROP。有效预防ROP将保护视力并改变早产儿的医疗管理。ROP由出生时氧合的突然增加引起，其在早产视网膜中产生相对高氧，导致超氧阴离子的过量产生。高氧还诱导过表达的精氨酸酶-1，这耗尽L-精氨酸，内皮一氧化氮（NO）合酶（ecNOS）的前体，从而阻断NO的合成和转移未偶联的ecNOS合成超氧化物。使这种超氧化物产生增加的是抗氧化酶如超氧化物歧化酶的个体发育缺陷。由此产生的视网膜超氧化物的相对丰富和NO的缺乏导致这两种自由基物质的失衡，从而使视网膜微循环血管收缩并诱导视网膜缺血。对缺血的反应进一步触发血管内皮生长因子（VEGF）的异常产生，其反过来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）有助于显着的视力障碍。ROP的成功预防需要同时补充NO和清除超氧化物。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种基于氧化还原的部分形成的新型药物：1）释放NO的有机硝基血管扩张剂部分，以及2）用作SOD模拟物、过氧化氢解毒的过氧化氢酶模拟物和过氧亚硝酸盐分解催化剂的硫辛酸部分。综上所述，R-200去除超氧化物并提供NO，而没有过氧亚硝酸盐形成的混淆效应。具体目的：确定R-200在临床相关新生鼠ROP模型中的疗效。我们将对暴露于70% O2 7天，然后暴露于室内空气10天的小鼠幼仔进行视网膜损伤的剂量反应研究。将在高氧暴露开始时开始R-200的预防性给药。我们预期R-200将：1）减轻形态学损伤，如RA和IVNV的视网膜平板评价的减少，和2）减少视网膜炎症和损伤，如视网膜脂质过氧化、VEGF浓度和过氧亚硝酸盐和聚（ADP-核糖）形成的减少。这些治疗效果预计将转化为临床改善，如RA和IVNV降低以及视力提高所反映的。 公共卫生关系： 早产儿视网膜病变是极低出生体重儿的主要并发症，并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疾病基本机制的新药，并将在临床相关的动物模型中测试这种药物。