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: 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
• 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' 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

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/文摘