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.

项目总结/摘要 威尔逊病（WD）是一种遗传性铜（Cu）超负荷疾病，由ATP 7 B基因突变引起， 这导致Cu的胆汁排泄减少。因此，WD以铜富集为特征， 肝细胞损伤WD临床表现为乏力、食欲不振、黄疸、急性肝硬化、 损伤和肝硬化，早在幼儿中，平均诊断年龄为9-10岁。然而，在这方面， 目前尚无有效的治疗方法。目前的治疗是基于减少肝铜 通过使用螯合剂（例如，D-青霉胺和曲恩汀） 或通过使用锌盐抑制肠Cu吸收。虽然有一个共识，铜螯合 在控制WD方面比饮食铜限制更有效，目前的铜螯合剂具有许多毒性， 包括胃肠道紊乱、骨髓抑制、感染、血小板减少、诱导自身免疫性 疾病和肝/肾功能障碍。考虑到WD的终身治疗，存在对新的治疗方法的未满足的需求。 治疗方法，以安全地消除多余的铜从肝脏。这一点对儿童尤为重要 因为治疗应在家庭确定的症状前儿童的诊断后开始 早在2至3岁时进行筛查，以防止进展为严重肝病。N，N '-双（2- 巯基乙基）苯甲酰胺（苯甲酰胺）是一种亲脂性二硫醇金属螯合剂， 用于治疗汞中毒。虽然醋甲酰胺没有显示出与药物相关的不良事件 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）仅在过量时。在初步实验中，我们发现， 在几种细胞中，新酰胺可减弱铜诱导的氧化应激，并逆转铜暴露引起的细胞毒性。 不同的细胞培养模型，包括肝细胞。这些数据表明，Emeramide可以去除过量的 铜从肝脏和改善肝损害与铜超载发生在WD患者。因此，在本发明中， 我们的目标是在拟议中的研究是确定在体内的疗效和毒性的醋酰胺在有毒的牛奶小鼠 其概括了人类的WD症状，并将结果与现有的Cu螯合剂进行比较。具体 目的是确定：1）绿酰胺是否减轻WD小鼠模型肝脏中的Cu沉积，和2）如果 与对照组相比，醋柳胺对铜超载具有保护肝脏的作用，沿着改善的安全性 与现有的铜螯合剂。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患者中与肝脏Cu蓄积相关的进行性肝病，特别是在预 有症状的孩子