A Thioredoxin Mimetic for Radiocontrast Nephropathy

用于放射性对比肾病的硫氧还蛋白模拟物

基本信息

批准号：
8308855
负责人：
Garry John Southan
金额：
$ 26.05万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8308855
关键词：
ATP Synthesis Pathway Acetylcysteine Acute Acute Kidney Failure Address Age Amides Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptosis Ascorbic Acid Attenuated Biochemical Biological Models Blood Bolus Infusion Breathing Calcium Channel Blockers Catalysis Cell Nucleus Cells Cleaved cell Clinical Clinical Research Complication Consensus Contrast Media Control Groups Cultured Cells Cysteine Cytoplasmic Protein Cytoprotective Agent DNA Repair Enzymes Dehydration Development Diabetes Mellitus Diagnostic Dialysis procedure Dopamine Dose Drug Exposure Drug Kinetics Elderly Enzyme Inhibitor Drugs Enzyme Inhibitors Equilibrium Event Exhibits Exposure to Fenoldopam Foundations Functional disorder Furosemide Gases Gelatinase A Genomics Glucose Glutathione Glutathione Disulfide Half-Life Head Histologic Histology Hour Hydration status Hypertension Image Immunologics Impairment In Vitro Incidence Infiltration Inflammation Inflammatory Injection of therapeutic agent Injury Intravenous Isotonic Exercise Kidney Kidney Diseases Kidney Failure Lipid Peroxidation Lung Mediating Medical Modality Modeling Mus NF-kappa B Necrosis Neutrophil Infiltration Normal saline Nuclear Nuclear Translocation Organ Ovalbumin Oxidants Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Patients Permeability Peroxonitrite Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Placebo Control Plasma Pneumonia Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Population Prevention Proline Prophylactic treatment Prostaglandin-Endoperoxide Synthase Randomized Rattus Regimen Renal Blood Flow Renal Tissue Renal function Renal tubule structure Reporting Resuscitation Risk Rodent Rodent Model Serum Single-Blind Study Single-Stranded DNA Sodium Bicarbonate Sprague-Dawley Rats Streptozocin Stress Sulfhydryl Compounds Technology Testing Theophylline Therapeutic Thioredoxin Tissues antidiuresis ascorbate base cell injury clinically relevant cytokine design diabetic diabetic rat high risk in vivo innovation intravenous injection kidney cell man mimetics nephrogenesis nitrosative stress novel oxidant stress oxidation patient population prevent professor prophylactic prospective renal ischemia response small molecule uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): We are developing a novel small molecule cytoprotective drug for the prevention of contrast-induced nephropathy (CIN) following intravenous radiocontrast media (CM) injection. CIN is mediated principally by CM-induced vasoconstriction of the afferent renal arteriololes, resulting in antidiuresis and severely compromised renal blood flow. The consequent renal ischemia induces oxidative and nitrosative stress, in particular within the nucleus of the renal tubules where DNA single strand breakage occurs. When this genomic injury is then recognized by the nuclear DNA repair enzyme poly (ADP-ribose) polymerase ("PARP"), NAD is cleaved to generate the product poly(ADP-ribose). Hyperactivation of PARP after CM injection depletes NAD stores, resulting in the loss of oxidative phosphorylation and interference with ATP synthesis. To address this unmet need, we are developing a cell-permeable thioredoxin mimetic (R-901), a thiol-rich tripeptide that is closely analogous to the native thioredoxin (TRX) motif. R-901 exhibits in vitro potency 450- and 50-fold > than N-acetylcysteine (NAC) and ascorbic acid, respectively, and in vivo potency substantially greater than NAC. Therapeutic administration of R-901 has been shown in a murine model of pulmonary inflammation (induced by ovalbumin sensitization and re-challenge) to reduce histologic injury, diminish leukocytic infiltration, attenuate tissue oxidation, block pr-inflammatory cytokine expression and nuclear translocation of NF-kB, diminish the degradation of the anti-inflammatory cytoplasmic protein IkBalpha, and restore the balance of reduced and oxidized forms of glutathione. In a murine LD100 model of severe redox stress induced by acute Cl2 gas inhalation, post-insult administration of R-901 reduced pulmonary neutrophil infiltration by 50%. Based on its ultrapotent catalysis of redox stress, and the critical relevance of redox stress to the pathophysiology of CIN, we now propose to construct a pharmacodynamic profile of R-901 in a rat model of CIN induced by dehydration, prostaglandin synthetase inhibition, and an IV challenge of CM. A sham injury group will be compared to treatment of CM-challenged rats with NAC or R-901 (over a one log dose range) initiated prior to CM administration under conditions of dehydration or volume loading. At 24 hours plasma will be analyzed for renal function and biochemical, histologic, and immunohistochemical parameters of renal injury. Renal and plasma concentrations of R-901 will be compared to assess tissue R-901 uptake. We expect that level of exposure to R-901 will correlate with the extent of tissue protection, as manifested by renal levels of necrosis (histology), lipid peroxidation, neutrophil infiltration, apoptosis, necrosis, peroxynitrite and poly(ADP- ribose) formation, and serum concentrations of neutrophil gelatinase-associated lipocalin. The proposed studies will provide a rational foundation for advanced commercial development of R-901, with the intent that this product will serve as first-line prophylaxis in high-risk patients undergoing CM injection. PUBLIC HEALTH RELEVANCE: Radiocontrast imaging is an invaluable and frequently used diagnostic modality for but its use is complicated by the subsequent development of kidney injury, often to the extent of requiring dialysis, particularly in populations at greatest risk, suh as the elderly, diabetic, and those with preexisting renal impairment. There are no approved pharmaceutical therapies to prevent this complication. We are developing a novel prophylactic agent that protects the kidney from radiocontrast administration by directly protecting kidney cells from injury. We now propose to test this agent in a clinically-relevant small animal model of radiocontrast-induced kidney failure.

描述（由申请人提供）：我们正在开发一种新型小分子细胞保护药物，用于预防静脉注射放射性造影剂（CM）后造影剂肾病（CIN）。 CIN 主要由 CM 诱导的传入肾小动脉血管收缩介导，导致抗利尿作用和肾血流严重受损。随后的肾缺血会引起氧化和亚硝化应激，特别是在发生 DNA 单链断裂的肾小管核内。当这种基因组损伤随后被核DNA修复酶聚(ADP-核糖)聚合酶(“PARP”)识别时，NAD被切割以生成产物聚(ADP-核糖)。注射 CM 后 PARP 过度激活，耗尽 NAD 储备，导致氧化磷酸化丧失并干扰 ATP 合成。为了解决这一未满足的需求，我们正在开发一种可渗透细胞的硫氧还蛋白模拟物 (R-901)，这是一种富含硫醇的三肽，与天然硫氧还蛋白 (TRX) 基序非常相似。 R-901 的体外效力分别是 N-乙酰半胱氨酸 (NAC) 和抗坏血酸的 450 倍和 50 倍，体内效力显着高于 NAC。 R-901 的治疗性给药已在小鼠肺部炎症模型（由卵清蛋白致敏和再攻击诱导）中显示，可减少组织学损伤、减少白细胞浸润、减弱组织氧化、阻断促炎细胞因子表达和 NF 核转位-kB，减少抗炎细胞质蛋白 IkBalpha 的降解，并恢复还原和氧化形式的平衡谷胱甘肽。在由急性 Cl2 气体吸入引起的严重氧化还原应激的小鼠 LD100 模型中，攻击后施用 R-901 将肺部中性粒细胞浸润减少了 50%。基于其对氧化还原应激的超强催化作用，以及氧化还原应激与 CIN 病理生理学的关键相关性，我们现在建议在脱水、前列腺素合成酶抑制和 CIN 诱导的大鼠模型中构建 R-901 的药效学特征。 IV CM的挑战。将假损伤组与在脱水或容量负荷条件下施用CM之前开始用NAC或R-901（超过一个对数剂量范围）的CM攻击大鼠的治疗进行比较。 24小时后，将分析血浆的肾功能以及肾损伤的生化、组织学和免疫组织化学参数。将比较 R-901 的肾脏和血浆浓度以评估组织 R-901 的吸收。我们预计 R-901 的暴露水平将与组织保护的程度相关，如肾坏死水平（组织学）、脂质过氧化、中性粒细胞浸润、细胞凋亡、坏死、过氧亚硝酸盐和聚（ADP-核糖）形成，和中性粒细胞明胶酶相关脂质运载蛋白的血清浓度。拟议的研究将为 R-901 的高级商业开发提供合理的基础，旨在使该产品成为接受 CM 注射的高危患者的一线预防药物。公众健康相关性：放射性对比成像是一种非常宝贵且经常使用的诊断方式，但其使用因肾损伤的后续发展而变得复杂，通常达到需要透析的程度，特别是在风险最大的人群中，例如老年人、糖尿病患者、以及那些先前存在肾功能不全的人。没有批准的药物疗法可以预防这种并发症。我们正在开发一种新型预防剂，通过直接保护肾细胞免受损伤来保护肾脏免受放射性对比剂的影响。我们现在建议在临床相关的小动物模型中测试这种药物放射性对比剂引起的肾衰竭。