Tissue-specific modulation of Apolipoprotein E in neurodegeneration

载脂蛋白 E 在神经变性中的组织特异性调节

• 批准号: 10457374
• 负责人: Chantal Ferguson
• 金额: $ 4.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457374
• 关键词: ALS pathology; Acetylgalactosamine; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapy; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Animal Behavior; Apolipoprotein E; Atherosclerosis; Behavior; Biological; Birth; Brain; Cellular biology; Characteristics; Chemicals; Chemistry; Cholesterol; Clinical; Data; Development; Disease; Disease Progression; Environmental Risk Factor; Etiology; Future; Genes; Genetic; Gliosis; Goals; Health; Healthcare Systems; Hepatic; High Density Lipoproteins; Homeostasis; Human; Impaired cognition; Individual; Injections; Knock-out; Knockout Mice; Lead; Learning; Lipids; Liver; Measures; Memory; Messenger RNA; Modeling; Motor; Motor Neurons; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Outcome Measure; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Plant Roots; Plasma; Production; Protein Isoforms; Provider; RNA Interference; Risk Factors; Serum; Site; Small Interfering RNA; Small RNA; Spinal Cord; Symptoms; Technology; Therapeutic; Tissues; Transgenic Organisms; Wild Type Mouse; Work; abeta deposition; age related neurodegeneration; clinical efficacy; design; efficacy testing; experience; improved; in vivo; innovation; lipid transport; mouse model; neuron loss; neuropathology; novel; presenilin-1; subcutaneous; superoxide dismutase 1; symptom management; therapeutic development; therapeutic target; therapeutically effective

PROJECT SUMMARY: Alzheimer’s Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) are multifaceted, progressive neurodegenerative conditions that place a monumental burden on patients, providers, and the public healthcare system. No disease-modifying treatments are currently available for either AD or ALS. Although the etiology of each disease is well studied, strategies targeting characteristic features of disease pathogenesis— e.g., beta-amyloid in AD—show limited clinical efficacy. Identification of novel targets that modify progression of neurodegeneration is needed for innovative therapeutic development across neurodegenerative disorders. AD and ALS are caused by genetic and environmental factors that alter downstream pathways like lipid homeostasis. A critical player in systemic and central nervous system (CNS) lipid transport, that is also implicated in the onset and progression of neurodegeneration, is apolipoprotein E (ApoE). Genetic deletion of ApoE reduces neuropathology in mice, but also causes atherosclerosis. Thus, despite its implication in disease, the diverse functionality of ApoE in its distinct biological “pools” (i.e. systemic and CNS) makes it a challenging therapeutic target. Reducing individual ApoE pools may circumvent this issue. However, the independent effects of systemic or CNS ApoE silencing on neurodegenerative diseases are unclear. The goal of this proposal is to determine the relationship between systemic and CNS ApoE pools, and their effects on disease progression in AD and ALS mice. The project will take advantage of chemically-stable, self- delivering small interfering RNAs (siRNAs) that enable sustained, tissue-specific silencing of target mRNA. GalNAc-siRNAs specifically deliver to liver (site of systemic ApoE production), and divalent (Di)-siRNAs deliver throughout the brain and spinal cord after intra-cerebroventricular (ICV) injection. With guidance from Drs. Anastasia Khvorova (siRNA chemistry), Robert Brown (ALS), Evgeny Rogaev (AD models), Andrew Tapper (animal behavior), and Thomas Smith (neuropathologist), GalNAc- and Di-siRNA will be used to silence hepatic and CNS ApoE, respectively, and the effects on CNS and systemic ApoE pools, and AD and ALS phenotypes, will be examined. In Aim 1, GalNAc-siRNA targeting ApoE will be subcutaneously injected into mice. In Aim 2, Di-siRNA targeting ApoE will be delivered to the CNS via ICV injection. Both aims will utilize the APP/PSEN1 mouse model of AD and the SOD1G93A mouse model of ALS, and will measure systemic and CNS ApoE and cholesterol levels, and AD and ALS neuropathology and behavior two months post injection. These studies will advance the understanding of how ApoE pools interact in the context of neurodegeneration, and the effects on disease progression. Such findings will inform strategies for safe and effective therapeutic targeting of ApoE in AD, ALS, and age-related neurodegenerative disorders.

项目总结： 阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)是多方面的、进行性的 神经退行性疾病给患者、提供者和公众带来巨大负担 医疗保健系统。目前还没有针对AD或ALS的疾病修正治疗方法。尽管 对每种疾病的病因都进行了充分的研究，针对疾病发病机制的特点制定了策略- 例如，阿尔茨海默病中的β-淀粉样蛋白-临床疗效有限。识别改变进程的新靶点 对于神经退行性疾病的创新治疗开发来说，神经退行性疾病是需要的。 AD和ALS是由遗传和环境因素引起的，这些因素改变了下游途径，如脂质 动态平衡。全身和中枢神经系统(CNS)脂质运输的关键参与者，也是 载脂蛋白E(ApoE)参与神经退行性变的发生和发展。遗传性缺失 APOE可减少小鼠的神经病理，但也会导致动脉粥样硬化。因此，尽管它隐含着 作为一种疾病，载脂蛋白E在其独特的生物“池”(即全身和中枢神经系统)中的不同功能使其成为 具有挑战性的治疗目标。减少单个ApoE池可能会绕过这个问题。然而， 全身性或中枢性载脂蛋白E沉默对神经退行性疾病的独立影响尚不清楚。 该提案的目标是确定系统和CNS ApoE池之间的关系，以及它们的 对AD和ALS小鼠疾病进展的影响。该项目将利用化学稳定、自我调节的 传递小干扰RNA(SiRNAs)，使靶基因持续的、组织特异性的沉默。 GalNAc-siRNAs特异性地递送到肝脏(全身性ApoE产生的部位)，二价(Di)-siRNAs递送 脑室内注射后遍及大脑和脊髓。 由Anastasia Khvorova博士(siRNA化学)、Robert Brown(ALS)、Evgeny Rogaev博士(AD)指导 模型)，Andrew Tapper(动物行为)和Thomas Smith(神经病理学家)，GalNAc-和Di-siRNA将 分别用于沉默肝脏和中枢ApoE，以及对中枢和全身ApoE池的影响，以及 AD和ALS的表型，将进行检查。在目标1中，靶向载脂蛋白E的GalNAc-siRNA将被皮下注射 注射到小鼠体内。在AIM 2中，靶向ApoE的Di-siRNA将通过脑室注射输送到中枢神经系统。这两个目标 将利用AD的APP/PSEN1小鼠模型和ALS的SOD1G93A小鼠模型，并将测量 全身性和中枢性载脂蛋白E和胆固醇水平，以及AD和ALS神经病理和行为两个月 注射后。这些研究将促进对载脂蛋白E池如何在 神经退行性变及其对疾病进展的影响。这些发现将为安全和安全的战略提供参考 载脂蛋白E在AD、ALS和年龄相关神经退行性疾病中的有效靶向治疗。