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

基本信息

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
项目类别：
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&apos 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

项目摘要

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/摘要威尔逊氏病（WD）是由ATP7B基因突变引起的一种遗传铜（CU）过载障碍，这导致胆汁排泄的Cu降低。结果，WD的特征是铜的积累和肝细胞损伤。 WD呈现各种临床症状，包括疲劳，厌食症，黄疸，急性肝脏损伤和肝肝硬化，早在诊断时平均年龄为9-10岁的幼儿。然而，迄今为止尚无有效的治疗方法。当前的治疗是基于肝铜的减少通过使用螯合剂（例如D-苯胺和Trientine）促进过量Cu的极端来存储。或通过抑制使用锌盐的肠受苦。虽然达成共识，即螯合比饮食CU在管理WD方面更有效，目前的Cu螯合剂具有多种毒性，包括胃肠道灾难，骨髓抑制，感染，血小板减少症，自身免疫性诱导疾病和肝脏/肾功能障碍。考虑到WD的终身治疗，对新的需要未满足治疗方法可以安全地从肝脏中清除多余的铜。这对儿童尤其重要因为应在家庭识别的症状前儿童诊断后开始治疗最早在2至3岁时进行筛查，以防止进展到严重的肝病。 n，n'bis（2- 胃乙基乙酰胺）（烯酰胺）是一种具有孤儿设计的亲脂性二硫醇金属螯合剂用于治疗汞毒性。虽然烯酰胺尚未显示出与药物相关的不良事件的迹象在动物和第1阶段和2A临床试验中，该药物还与几种有毒金属（铅和镉）结合以及养分金属（铁和铜）仅在过量时。在初步实验中，我们发现烯酰胺减弱了Cu诱导的氧化应激和由CU暴露引起的逆转细胞毒性不同的细胞培养模型，包括肝细胞。这些数据表明伊氨酰胺可以消除多余的来自肝脏的CU并改善与WD患者发生的CU过载相关的肝损伤。那，我们在拟议的研究中的目标是确定厄米特酰胺在有毒牛奶小鼠中的体内效率和毒性这概括了人类中的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）如果Emeramide减轻了WD小鼠模型的肝脏中的Cu沉积和2） Emeramide提供了针对CU超载的肝保护作用，并进行了改进的安全概况。与现有的Cu螯合剂。我们的投资将提供一种新的治疗策略，可能是预防疾病，避免在WD患者中与肝Cu积累相关的进行性肝病，尤其是在前有症状的孩子。