Oral Gene Delivery to Improve Iron Overload Disorders

口服基因递送改善铁过载疾病

基本信息

批准号：
9173116
负责人：
Mansoor M Amiji
金额：
$ 19.04万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9173116
关键词：
Accounting Adverse effects Affect Agranulocytosis Alzheimer&apos s Disease American Anemia Area Arthralgia Arthritis Auditory Blood Blood Cells Blood Transfusion Bone Marrow Brain Cardiomyopathies Cellular Metabolic Process Cessation of life Chelating Agents Chronic Colitis Defect Deferoxamine Deposition Diabetes Mellitus Diet Dietary Iron Disease Dose Drosophila pros protein Drug Kinetics Drug or chemical Tissue Distribution Duodenum Dysmyelopoietic Syndromes Encapsulated Epithelium Erythrocytes Erythropoiesis Ferritin Figs - dietary Formulation Gene Delivery Gene Silencing Genes Genetic Polymorphism Healthcare Heart Heart Hypertrophy Heart failure Heme Hemochromatosis Hemoglobin Hereditary Disease Hereditary hemochromatosis Human Hypertriglyceridemia Hypertrophy Inflammatory Intervention Intestinal Absorption Intestines Iron Iron Metabolism Disorders Iron Overload Kinetics Knockout Mice Liver Liver Cirrhosis Mediating Metabolism Metals Methods Microspheres Modeling Mus Musculoskeletal Mutation Nanotechnology Neurodegenerative Disorders Neutropenia Nutrient Oncogenic Oral Oral Administration Oxidation-Reduction Oxidative Stress Parkinson Disease Pathogenesis Play Population Production Property Proteins Radioactivity Reporting Risk Factors Role SLC11A2 gene Sickle Cell Anemia Site Small Interfering RNA Solubility System TNF gene Thalassemia Therapeutic Tissues Toxic effect Traumatic Brain Injury Treatment Efficacy Up-Regulation Venous blood sampling Western Blotting Wild Type Mouse absorption base caucasian American cytokine gastrointestinal gene therapy improved in vivo inhibitor/antagonist lipid metabolism metal transporting protein 1 microcytic/hypochromic anemia mouse model nanoparticle neurotoxicity novel novel therapeutic intervention premature small molecule therapeutic target uptake

项目摘要

PROJECT SUMMARY/ABSTRACT High iron stores are a well-defined risk factor for the pathogenesis of several diseases, including heart failure, liver cirrhosis, arthritis, diabetes and hypertriglyceridemia. Iron overload is best represented by hereditary hemochromatosis (HH), one of the most common genetic diseases in the North American Caucasian population, which is characterized by elevated intestinal absorption and progressive tissue deposition of iron. Polymorphisms in the HFE (High Fe) gene are the leading cause of HH, accounting for 7-32% in North American populations. Iron overload also occurs in blood transfusion, which is required for several anemias (e.g. thalassemia, sickle cell anemia) due to defects in blood cell metabolism. Notably, high iron stores in the brain are associated with several neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s diseases) and some pathological conditions, including traumatic brain injury. Iron chelators, such as deferoxamine and deferasirox, are clinically used to reduce iron burden, but the use of chelators is limited by a number of significant side effects, including agranulocytosis, neutropenia, ocular/auditory toxicities, musculoskeletal-joint pains, gastrointestinal disturbances and even death. Considering hundreds of millions of people affected by various types of iron overload, there are unprecedented needs for a new therapeutic strategy by controlling the transport of iron in the body. While the Divalent Metal Transporter 1 (DMT1) plays a well-established role in the absorption of iron as an essential nutrient from diet, up-regulation of intestinal DMT1 is associated with HH in both humans and mice. Since DMT1 is also required for red cell production in the bone marrow, a “selective” suppression of intestinal DMT1 can be an excellent therapeutic target by direct delivery of DMT1 inhibitors to the site of absorption (i.e. oral administration) with no systemic effects. Although a few small molecule-based DMT1 inhibitors have been studied, overall enthusiasm is low because these inhibitors “indirectly” alter DMT1 function, for example, by modifying redox status, as well as their unfavorable in vivo pharmacokinetic properties (poor solubility and rapid metabolism). Gene silencing has increased therapeutic potential to selectively decrease the levels of unwanted molecules, such as oncogenic proteins and pro-inflammatory cytokines. We have recently demonstrated that intestinal TNFα was significantly down-regulated in a mouse model of colitis after oral administration of siRNA in nanoparticles-in-microspheres (NMs), which improved colitis conditions. Thus, the major underlying hypothesis is that oral DMT1 silencing by siRNA-encapsulated NMs decreases intestinal uptake of dietary iron and improves iron overload and iron-mediated toxicity. The specific aims of this study are focused on 1) developing and validating DMT1 siRNA/NMs to inhibit intestinal iron transporters and iron absorption and 2) evaluating the therapeutic efficacy of DMT1 siRNA/NMs using a mouse model of iron overload. Overall, this strategy provides a selective and effective method to support therapeutic benefits over numerous iron overload disorders by a combination of siRNA and nanotechnology.

项目概要/摘要高铁储备是多种疾病发病机制的明确危险因素，包括心力衰竭、肝硬化、关节炎、糖尿病和高甘油三酯血症最典型的是遗传性的。血色素沉着症（HH），北美白种人最常见的遗传病之一其特征是铁的肠道吸收增加和进行性组织沉积。 HFE（高铁）基因多态性是导致HH的主要原因，在北方地区占7-32% 美国人的铁超载也发生在输血中，这是几种贫血症所必需的。（例如地中海贫血、镰状细胞性贫血）由于血细胞代谢缺陷而引起。大脑与多种神经退行性疾病（例如阿尔茨海默病和帕金森病）有关一些病理状况，包括创伤性脑损伤，如去铁胺和铁螯合剂。地拉罗司在临床上用于减少铁负荷，但螯合剂的使用受到许多因素的限制显着的副作用，包括粒细胞缺乏症、中性粒细胞减少症、眼/听觉毒性、肌肉骨骼关节考虑到数亿人受到影响。各种类型的铁超负荷，前所未有地需要通过控制铁超负荷的新治疗策略而二价金属转运蛋白 1 (DMT1) 在铁的体内转运中发挥着重要作用。铁作为饮食中必需营养素的吸收，肠道 DMT1 的上调与 HH 相关由于 DMT1 也是骨髓中红细胞生成所必需的，因此具有“选择性”。通过直接将 DMT1 抑制剂递送至肠道，抑制肠道 DMT1 可以成为极好的治疗靶点。尽管有一些基于小分子，但吸收部位（即口服给药）没有全身作用。 DMT1抑制剂已被研究，总体热情较低，因为这些抑制剂“间接”改变DMT1 功能，例如，通过改变氧化还原状态，以及它们不利的体内药代动力学特性（溶解度差和快速代谢）。基因沉默增加了治疗潜力。选择性降低不需要的分子的水平，例如致癌蛋白和促炎蛋白我们最近证明小鼠肠道 TNFα 显着下调。口服微球中的纳米粒子 (NM) 中的 siRNA 后的结肠炎模型，该模型改善了因此，主要的潜在假设是 siRNA 封装的口服 DMT1 沉默。 NM 减少肠道对膳食铁的吸收，改善铁过载和铁介导的毒性。本研究的具体目标集中在 1) 开发和验证 DMT1 siRNA/NM 来抑制肠道铁转运蛋白和铁吸收，2) 使用总体而言，该策略提供了一种选择性且有效的方法来支持。 siRNA 和纳米技术相结合，对多种铁超载疾病具有治疗效果。