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：
10710203
负责人：
Swati Betharia
金额：
$ 21.84万
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/10710203
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 Blood 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 Marketing Mediating Mercury Metals Milk Mitochondria Modeling Morbidity - disease rate Multiple System Atrophy Mus Mutation Myelosuppression Nutrient Oral Oral Administration Organ Orphan Drugs Outcome Oxidative Stress Oxidative Stress Induction 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 Survival Rate Symptoms Testing Thrombocytopenia Time Tissues Toddler Toxic effect Translating Treatment Efficacy Triethylenetetramine Urine Wilson disease protein Zinc absorption acute liver injury cell injury chelation cofactor cytotoxicity dietary dietary restriction disorder prevention dithiol effective therapy experimental study exposed human population follow-up gastrointestinal hepatoprotective improved in vivo kidney dysfunction lead exposure lipophilicity liver function liver injury metal chelator metal metabolism mortality mouse model neuroprotection 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.

项目概要/摘要威尔逊病 (WD) 是一种遗传性铜 (Cu) 超载疾病，由 ATP7B 基因突变引起，导致铜的胆汁排泄减少，因此，WD 的特点是铜积累和肝细胞损伤会出现各种临床症状，包括疲劳、厌食、黄疸、急性肝病等。损伤和肝硬化，最早在诊断时平均年龄为 9-10 岁的幼儿中出现。迄今为止尚无有效的治疗方法，目前的治疗方法是减少肝脏铜。通过使用螯合剂（例如 D-青霉胺和曲恩汀）促进过量铜的排泄来储存或通过使用锌盐抑制肠道铜吸收，而铜螯合已成为共识。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，包括胃肠道紊乱、骨髓抑制、感染、血小板减少、诱导自身免疫考虑到 WD 的终身治疗，对新药物的需求尚未得到满足。从肝脏安全清除多余铜的治疗方法这对儿童尤其重要。因为对于家人发现的症状前儿童，应在诊断后开始治疗尽早在 2 至 3 岁时进行筛查，以防止进展为严重肝病。巯基乙基)间苯二甲酰胺 (emeramide) 是一种亲脂性二硫醇金属螯合剂，具有孤儿药资格用于治疗汞中毒，而 emeramide 尚未显示出与药物相关的不良事件的迹象。在动物体内以及 1 期和 2a 期临床试验中，该药物还与多种有毒金属（铅和镉）结合以及营养金属（铁和铜），仅在过量时才存在。在初步实验中，我们发现。 emeramide 可减轻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 可以去除过量的细胞。来自肝脏的 Cu 并改善 WD 患者发生的与 Cu 超负荷相关的肝损伤。我们拟议研究的目标是确定 Emeramide 对有毒牛奶小鼠的体内功效和毒性重现人类 WD 症状，并将结果与现有的铜螯合剂进行比较。目的是确定：1) emeramide 是否可以减轻 WD 小鼠模型肝脏中的铜沉积；2) 是否可以 emeramide 具有针对铜过载的保肝作用，并且与相比，安全性更高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 患者出现与肝脏铜积累相关的进行性肝病，尤其是在治疗前有症状的儿童。