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.

项目摘要/摘要高铁存储是多种疾病的发病机理的明确定义的危险因素，包括心力衰竭，肝肝硬化，关节炎，糖尿病和高甘油三酯血症。铁超载最好由世袭代表血色素沉着症（HH），北美高加索人最常见的遗传疾病之一人口的特征是铁的肠道滥用和进行性组织沉积升高。 HFE（高铁）基因的多态性是HH的主要原因，北部占7-32％美国人口。铁超负荷也发生在输血中，这是几种贫血所必需的（例如，Thalassya，镰状细胞贫血），由于血细胞代谢缺陷。值得注意的是，高铁存储在大脑与几种神经退行性疾病有关（例如，阿尔茨海默氏症和帕金森氏病）和一些病理状况，包括脑外伤。铁螯合剂，例如脱氧胺和 deferasirox在临床上用于减少铁伯南，但螯合剂的使用受到许多限制重要的副作用，包括粒细胞增多症，中性粒细胞减少，眼/听觉毒性，肌肉骨骼 - 骨骼结合痛苦，胃肠道灾难甚至死亡。考虑了数亿人受影响的人各种各样的铁超载，通过控制新的治疗策略有前所未有的需求铁在体内的运输。而二价金属转运蛋白1（DMT1）在铁作为饮食中必不可少的营养素的吸收，肠道DMT1的上调与HH有关人类和老鼠。由于骨髓中的红细胞产生也需要DMT1，因此“选择性” 通过将DMT1抑制剂直接递送到没有全身影响的滥用部位（即口服给药）。虽然有几个小分子 DMT1抑制剂已经研究了，总体热情很低，因为这些抑制剂“间接”改变了DMT1 功能，例如，通过修改氧化还原状态以及它们在体内药代动力学不利的功能性质（可溶性和快速代谢）。基因沉默具有增加的治疗潜力有选择地降低不需要分子的水平，例如致癌蛋白和促炎性蛋白细胞因子。我们最近证明，肠TNFα在小鼠中显着下调口服siRNA在纳米粒子中的siRNA后结肠炎模型（NMS），改善结肠炎条件。这是主要的基本假设是siRNA包裹的口服DMT1沉默 NMS减少了饮食铁的肠道摄取，并改善了铁超载和铁介导的毒性。这这项研究的具体目的集中于1）开发和验证DMT1 siRNA/NMS以抑制肠道铁运输蛋白和铁滥用以及2）使用A评估DMT1 siRNA/NMS的治疗效率铁超负荷的鼠标模型。总体而言，该策略提供了一种选择性有效的方法来支持通过siRNA和纳米技术的结合，治疗对许多铁超负荷疾病的益处。