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Albumin hitchhiking siRNAs for gene targeting in aged brain

白蛋白搭便车 siRNA 用于老年大脑基因靶向

基本信息

批准号：
10467737
负责人：
Craig Lewis Duvall
金额：
$ 22.98万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10467737
关键词：
Abraxane Address Affinity Age Age-Months Aging Albumins Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Arthritis Binding Biodistribution Biological Biological Assay Biological Availability Blood Blood - brain barrier anatomy Blood Circulation Blood Vessels Body Weight decreased Brain Bypass C57BL/6 Mouse Cells Cholesterol Clinical Custom Data Degenerative polyarthritis Deposition Dose Drug Delivery Systems Drug Formulations Drug Kinetics Exhibits Fatty Acids Fibrinogen Flow Cytometry Functional disorder Gene Silencing Gene Targeting Genes Genetic Genotype Goals Half-Life Hepatotoxicity Histology Hour Housekeeping Gene Human Hydrophobicity Incidence Individual Inflammatory Intravenous Knee Knee joint Levemir Life Expectancy Link Lipids Lipoprotein Binding Malignant Neoplasms Mediating Messenger RNA Modeling Mus Neurodegenerative Disorders Neurons Organ Outcome Pathologic Penetrance Pharmaceutical Preparations Plasma Positioning Attribute Procedures Property Proteins Publishing Reagent Research Route Scheme Serum Serum Proteins Site Small Interfering RNA Specificity Time Tissues Toxic effect Western Blotting Wild Type Mouse Work aged aging brain base blood-brain barrier disruption brain cell brain tissue cell type cytokine density efficacy study experience genetic risk factor improved in vivo intravenous administration knock-down mouse model nephrotoxicity neurovascular novel novel strategies personalized medicine precision medicine prevent side effect stem treatment strategy tumor uptake

项目摘要

A current hurdle for the treatment of Alzheimer’s disease (AD) is administration of efficacious doses of biological drugs in the brain. The strongest risk factor for AD is aging, which coincides with progressive dysfunction of the blood-brain barrier (BBB) leading to entry and retention of serum proteins that are normally excluded from healthy brain. One of these proteins is albumin, which is not detected in young brain tissue but gradually accumulates in the brain with age. Here, we propose to a novel strategy for treating AD that will leverage albumin as a “natural” carrier to enhance siRNA-mediated gene targeting in the aged brain. We hypothesize that “hitchhiking” siRNA onto albumin will improve siRNA accumulation and gene silencing activity in the aged brain after intravenous administration, thereby providing a customizable strategy to target genes associated with AD. This approach is facilitated by a novel diacyl fatty acid carrier developed in our lab (“EG18”) that can be directly conjugated to siRNA (“siRNA-EG18”). We have relevant preliminary data showing that: 1) siRNA-EG18 has enhanced affinity and specificity for albumin and increased circulation half-life relative to our previously published siRNA-L2 carrier; 2) siRNA-EG18 exerts sustained gene knockdown in a mouse model of osteoarthritis that leads to albumin accumulation in the inflamed knee joint; 3) siRNA-EG18 accumulates in the brains of old but not young mice 24 hours after intravenous delivery of a modest 1 mg/kg dose. Aim 1 of this proposal will build on these results by examining the pharmacokinetics, biodistribution, and toxicity of siRNA-EG18 as a function of age and dosing scheme. Aim 2 will examine the bioactivity of siRNA-EG18 in the aged brain, with a focus on targeting APOE, the strongest known genetic risk factor for AD. Collectively, this proposal will establish working parameters for achieving gene silencing in the aged brain via albumin hitchhiking of siRNA, thereby providing new opportunities for personalized medicine in AD.

治疗阿尔茨海默病（AD）的当前障碍是在脑中施用有效剂量的生物药物。AD的最强风险因素是衰老，这与血脑屏障（BBB）的进行性功能障碍相一致，导致通常从健康大脑中排除的血清蛋白进入和保留。其中一种蛋白质是白蛋白，它在年轻的脑组织中检测不到，但随着年龄的增长逐渐积累在大脑中。在这里，我们提出了一种治疗AD的新策略，该策略将利用白蛋白作为“天然”载体来增强siRNA介导的老年大脑中的基因靶向。我们假设，“搭便车”siRNA到白蛋白将改善siRNA积累和基因沉默活性在老年人的大脑静脉注射后，从而提供了一个可定制的策略，以靶向与AD相关的基因。该方法通过我们实验室开发的新型二酰基脂肪酸载体（“EG 18”）来促进，该载体可以直接缀合至siRNA（“siRNA-EG 18”）。我们有相关的初步数据显示：1）siRNA-EG 18相对于我们先前公开的siRNA-L2载体具有增强的对白蛋白的亲和力和特异性以及增加的循环半衰期; 2)siRNA-EG 18在骨关节炎小鼠模型中发挥持续的基因敲除作用，导致炎症膝关节中白蛋白积聚; 3）静脉注射适度的1 mg/kg剂量后24小时，siRNA-EG 18在老年小鼠而不是年轻小鼠的大脑中积聚。本提案的目的1将通过检查siRNA-EG 18作为年龄和给药方案的函数的药代动力学、生物分布和毒性来建立这些结果。目的2将检查siRNA-EG 18在老年大脑中的生物活性，重点是靶向APOE，这是已知的AD最强的遗传风险因素。总的来说，这项提案将建立工作参数，通过白蛋白搭便车的siRNA实现老年大脑中的基因沉默，从而为AD的个性化药物提供新的机会。