Intranasal gene delivery for Alzheimer’s disease

鼻内基因递送治疗阿尔茨海默病

基本信息

批准号：
10308277
负责人：
Mansoor M Amiji
金额：
$ 44.51万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308277
关键词：
APP-PS1 Affect Agranulocytosis Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Amyloid beta-Protein Area Arthritis Auditory Biodistribution Brain Cardiomyopathies Cations Chelating Agents Clinical Deposition Development Diabetes Mellitus Diet Disease Dysmyelopoietic Syndromes Encapsulated Erythrocytes Exhibits Formulation Gastrointestinal Hemorrhage Gene Combinations Gene Delivery Gene Silencing Genes Hemoglobinopathies Hereditary hemochromatosis Huntington Disease Hypertriglyceridemia Impairment Infection Inflammatory Intestines Intranasal Administration Iron Iron Chelating Agents Iron Metabolism Disorders Iron Overload Kidney Failure Label Liposomes Liver Cirrhosis Liver Fibrosis Luciferases Mammals Memory impairment Messenger RNA Metabolic Diseases Metals Molecular Mus Nanotechnology Nasal Epithelium Nerve Degeneration Neurodegenerative Disorders Neurons Neutropenia Nucleic Acids Oncogenic Oxidative Stress Parkinson Disease Patients Production Property Proteins Reporter Genes Risk Factors Route Safety Sickle Cell Anemia Site Small Interfering RNA Symptoms TNF gene Tachycardia Testing Thalassemia Therapeutic Tissues Toxic effect Toxicity Tests Transfection Transgenes Treatment Efficacy Visual Western Blotting base cytokine efficacy evaluation gene therapy improved in vivo interest iron metabolism macrophage metal transporting protein 1 microcytic anemia molecular phenotype motor deficit mouse model nanoparticle nervous system disorder neurobehavioral neuroinflammation novel novel therapeutic intervention oxidative damage protein expression therapeutic target transgene delivery uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Iron overload disorders, including hereditary hemochromatosis (HH) and transfusional hemoglobinopathies (e.g. thalassemia, myelodysplastic syndrome, sickle cell anemia), affect tens of millions of people worldwide. Iron overload is a well-defined risk factor for the development and progression of several metabolic diseases, including cardiomyopathy, liver cirrhosis, arthritis, diabetes and hypertriglyceridemia. Importantly, increased iron stores in the brain are closely associated with neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s and Huntington’s diseases). Although iron chelators are efficient to remove excess iron from the body, they exhibit significant toxicities, including gastrointestinal bleeding, agranulocytosis, infection, tachycardia, kidney failure and liver fibrosis. Moreover, there is no chelator that effectively restores inappropriately high iron in the brain of patients with neurodegenerative diseases. Hence, there is an unmet need for a new therapeutic strategy by controlling the transport of iron in the brain. Ferroportin (FPN) is the primary iron transporter responsible for the export of intracellular iron. Since FPN is also essential for intestinal iron uptake from diet as well as iron release from the macrophages to recycle the metal for red blood cell production, tissue-specific modulation of FPN can be an excellent therapeutic target to modify brain iron transport with minimal systemic effects. Gene therapy can potentially protect against a number of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, by delivering nucleic acid encoding for therapeutic molecules. Conversely, gene silencing selectively decreases the levels of unwanted molecules, such as oncogenic proteins and pro-inflammatory cytokines. We have recently demonstrated that intranasal administration of mRNA in nanoparticles significantly up-regulated protein expression of the reporter genes, such as luciferase and GFP, in the brain. These results suggested that in vivo gene delivery can be exploited in the area of iron disorders, and further prompted us to inquire if a direct delivery of FPN transgene to the brain (site of action) via the intranasal route can mobilize brain iron stores, while avoiding off-target effects. Thus, our hypothesis is that intranasal administration of FPN mRNA in cationic liposomes (CL) enhances brain FPN expression, increases efflux of iron out of the brain and ameliorates iron-induced neuronal impairments. The specific aims are focused on 1) developing and validating FPN transgene/CL to increase brain FPN levels and iron efflux and 2) evaluating the therapeutic efficacy of FPN transgene/CL using a mouse model of iron-associated Alzheimer’s disease. Overall, this strategy provides a selective, effective and safe approach for gene therapy in the area of iron-catalyzed neurodegenerative and other types of neurological disorders.

项目摘要/摘要铁超负荷疾病，包括遗传性血色素症（HH）和输血血红蛋白病（例如， Thalassya，骨髓增生综合征，镰状细胞贫血）影响了全球数千万人。铁超负荷是明确定义的多种代谢疾病发展和发展的风险因素，包括心肌病，肝硬化，关节炎，糖尿病和高甘油三酯血症。重要的是，铁增加大脑中的商店与神经退行性疾病密切相关（例如，阿尔茨海默氏症，帕金森氏症和亨廷顿的疾病）。尽管铁螯合剂有效地从身体中去除多余的铁，但它们暴露了重大战术，包括胃肠道出血，农业细胞增多症，感染，心动过速，肾衰竭和肝纤维化。此外，没有螯合剂有效地恢复了大脑中不适当的铁神经退行性疾病的患者。因此，通过控制铁在大脑中的运输。铁蛋白（FPN）是负责的主要铁运输蛋白细胞内铁的出口。由于FPN对于饮食中的肠道摄取以及释放也是必不可少的从巨噬细胞回收金属以产生红细胞的金属，组织特异性调节FPN可以成为以最小的全身效应来修饰脑铁运输的出色治疗靶标。基因疗法可以有可能保护许多神经退行性疾病，包括阿尔茨海默氏症，帕金森氏症和亨廷顿的疾病，通过为治疗分子提供核酸编码。相反，基因沉默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。我们最近证明了纳米颗粒中mRNA的鼻内给药显着在大脑中，报告基因（例如荧光素酶和GFP）上调的蛋白质表达。这些结果建议可以在铁疾病区域探索体内基因的递送，并进一步促使我们提出询问FPN是否直接传递到大脑（作用部位）是否通过鼻内路线转化可以动员大脑铁存储，同时避免脱靶效应。这是我们的假设是鼻内给药FPN mRNA 在阳离子脂质体（CL）中，增强了脑FPN的表达，增加了铁从大脑中排出，并且减轻铁引起的神经元损伤。具体目标的重点是1）开发和验证 FPN转基因/CL以增加脑FPN水平和铁外排，2）评估FPN的治疗效率使用与铁相关的阿尔茨海默氏病小鼠模型转基因/CL。总体而言，该策略提供了在铁催化的神经退行性和其他类型的神经系统疾病。