Reversal of copper accumulation for the early prevention of Wilson’s disease

逆转铜积累以早期预防威尔逊病

• 批准号: 10573600
• 负责人: Swati Betharia
• 金额: $ 19.34万
• 依托单位: UNIVERSITY OF MASSACHUSETTS LOWELL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-27 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10573600
• 关键词: 10 year old; 3 year old; Acute; Adverse event; Affect; Age; Alkaline Phosphatase; Animals; Anorexia; Antioxidants; Attenuated; Autoimmune Diseases; Autophagocytosis; Bile fluid; Biliary; Bilirubin; Binding; Biological Markers; Bone Marrow Suppression; Brain; Cadmium; Cell Culture Techniques; Cells; Chelating Agents; Child; Chronic; Cirrhosis; Clinical; Clinical Chemistry; Clinical Research; Clinical Trials; Consensus; Cooley' s anemia; Copper; Copper Chelation; Data; Deposition; Diagnosis; Dietary Intervention; Disease; Disease Progression; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Early Intervention; Excretory function; Exhibits; Eye; Family; Fatigue; Genes; Glutathione; Goals; HepG2; Hepatic; Hepatocyte; Hepatolenticular Degeneration; Hepatotoxicity; Hereditary Disease; Human; Icterus; Inductively Coupled Plasma Mass Spectrometry; Infection; Inherited; Intestines; Investigation; Iron; Iron Overload; Kidney; Lead; Life; Liver; Liver Cirrhosis; Liver Dysfunction; Liver Failure; Liver diseases; Malondialdehyde; Mediating; Mercury; Metals; Milk; Mitochondria; Modeling; Morbidity - disease rate; Multiple System Atrophy; Mus; Mutation; Myelosuppression; Nutrient; Oral; Organ; Orphan Drugs; Outcome; Oxidative Stress; Parkinson Disease; Patients; Penicillamine; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Physiology; Pilot Projects; Prevalence; Prevention; Primary carcinoma of the liver cells; Progressive Supranuclear Palsy; Proteins; Radioisotopes; Research; Respiration; Safety; Salts; Serum; Sulfhydryl Compounds; Survival Rate; Symptoms; Testing; Thrombocytopenia; Time; Tissues; Toddler; Toxic effect; Translating; Treatment Efficacy; Triethylenetetramine; Urine; Wilson disease protein; Zinc; absorption; acute liver injury; base; cell injury; chelation; cofactor; cytotoxicity; dietary; dietary restriction; disorder prevention; effective therapy; experimental study; exposed human population; follow-up; gastrointestinal; improved; in vivo; kidney dysfunction; lead exposure; lipophilicity; liver function; liver injury; metal chelator; metal metabolism; mortality; mouse model; novel therapeutic intervention; pediatric patients; prevent; response; screening; side effect; toxic metal

PROJECT SUMMARY/ABSTRACT Wilson’s disease (WD) is an inherited copper (Cu) overload disorder caused by mutations in the ATP7B gene, which result in decreased biliary excretion of Cu. As a result, WD is characterized by copper accumulation and liver cell damage. WD presents with various clinical symptoms, including fatigue, anorexia, jaundice, acute liver injury and liver cirrhosis, as early as in toddlers with an average age of 9-10 years old at diagnosis. However, there is no effective treatment available to date. The current treatment is based on the reduction in hepatic Cu stores either by facilitating the excretion of excess Cu using chelating agents (e.g., D-penicillamine and trientine) or by inhibiting the intestinal Cu absorption using zinc salts. While there has been a consensus that Cu chelation is more effective than dietary Cu restriction in managing WD, current Cu chelators have a number of toxicities, including gastrointestinal disturbance, myelosuppression, infection, thrombocytopenia, induction of autoimmune diseases, and liver/kidney dysfunction. Considering life-long treatment of WD, there is an unmet need for a new therapeutic approach to safely remove excess Cu from the liver. This is particularly important for children because the treatment should be initiated upon diagnosis in pre-symptomatic children identified by family screening as early as 2 to 3 years of age, in order to prevent progression to severe liver disease. N,N’-bis(2- mercaptoethyl)isophthalamide (emeramide) is a lipophilic di-thiol metal chelator that has orphan drug designation for the treatment of mercury toxicity. While emeramide has shown no indication of drug-related adverse events in animals and in Phase 1 and 2a clinical trials, the drug also binds to several toxic metals (lead and cadmium) as well as nutrient metals (iron and copper) only when in excess. In preliminary experiments, we found that emeramide attenuated Cu-induced oxidative stress and reversed cytotoxicity caused by Cu exposure in several different cell culture models, including hepatocytes. These data suggest that emeramide could remove excessive Cu from the liver and improve liver damage associated with Cu overload occurring in patients with WD. Thus, our goal in the proposed research is to determine the in vivo efficacy and toxicity of emeramide in toxic milk mice that recapitulate WD symptoms in humans and to compare the results with existing Cu chelators. The specific aims are to determine: 1) if emeramide mitigates Cu deposition in the liver of a mouse model of WD and 2) if emeramide provides hepatoprotective effects against Cu overload along with improved safety profiles compared with existing Cu chelators. Our investigation will provide a new therapeutic strategy, likely disease prevention, to avoid progressive liver disease associated with hepatic Cu accumulation in WD patients, especially in pre- symptomatic children.

项目摘要/摘要 威尔逊病(WD)是一种遗传性铜(铜)超负荷疾病，由ATP7B基因突变引起， 这会导致胆汁中铜的排泄减少。因此，WD的特征是铜的聚集和 肝细胞受损。WD表现为各种临床症状，包括乏力、食欲不振、黄疸、急性肝病。 损伤和肝硬变，最早在学步儿童中确诊，平均年龄为9-10岁。然而， 到目前为止还没有有效的治疗方法。目前的治疗是基于降低肝脏中的铜 通过使用螯合剂(例如，D-青霉胺和三乙胺)促进过量铜的排泄来储存铜 或使用锌盐抑制肠道铜的吸收。虽然人们已经达成共识，铜的络合作用 在控制WD方面比饮食铜限制更有效，目前的铜螯合剂有许多毒性， 包括胃肠功能障碍、骨髓抑制、感染、血小板减少、诱导自身免疫 疾病，以及肝/肾功能障碍。考虑到WD的终身治疗，有一种新的需求尚未得到满足 安全清除肝脏中过量铜的治疗方法。这对孩子们来说尤其重要 因为治疗应该在家人确认的有症状的儿童确诊后开始 最早在2至3岁时进行筛查，以防止进展为严重的肝病。N，N‘-双(2- (硫乙基)异苯二甲酰胺是一种亲脂性的二硫醇金属螯合剂，具有孤儿药物名称。 用于治疗汞中毒。虽然艾美拉胺没有显示出与药物有关的不良事件的迹象 在动物试验以及1期和2a期临床试验中，该药物还与几种有毒金属(铅和镉)结合。 以及营养金属(铁和铜)，只有在过量的时候。在初步实验中，我们发现 艾美拉胺减轻铜诱导的氧化应激并逆转铜暴露所致的细胞毒性 不同的细胞培养模式，包括肝细胞。这些数据表明，艾美拉胺可以清除多余的 从肝脏中提取铜，并改善与WD患者铜超载相关的肝损害。因此， 我们在这项拟议的研究中的目标是确定艾美拉胺对中毒乳鼠的体内疗效和毒性。 这概括了人类的WD症状，并将结果与现有的铜络合剂进行比较。具体的 目的是确定：1)艾美拉胺是否能减轻WD模型小鼠肝脏中铜的沉积；2)是否 与对照相比，艾美拉胺对铜超载具有保护肝脏的作用，同时改善了安全性 与现有的铜络合剂。我们的研究将提供一种新的治疗策略，可能是疾病预防， 避免WD患者与肝脏铜蓄积相关的进行性肝病，特别是在 有症状的儿童。