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：
10611521
负责人：
Craig Lewis Duvall
金额：
$ 19万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611521
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 Vessels Blood brain barrier dysfunction Body Weight decreased Brain Bypass C57BL/6 Mouse Cells Cholesterol Circulation Clinical Custom Data Degenerative polyarthritis Deposition Dose Drug Delivery Systems Drug Formulations Drug Kinetics Exclusion Exhibits Fatty Acids Fibrinogen Flow Cytometry 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 apolipoprotein E-3 apolipoprotein E-4 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

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 Vessels Blood brain barrier dysfunction Body Weight decreased Brain Bypass C57BL/6 Mouse Cells Cholesterol Circulation Clinical Custom Data Degenerative polyarthritis Deposition Dose Drug Delivery Systems Drug Formulations Drug Kinetics Exclusion Exhibits Fatty Acids Fibrinogen Flow Cytometry 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 apolipoprotein E-3 apolipoprotein E-4 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

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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.

治疗阿尔茨海默氏病（AD）的当前障碍是给予大脑中有效剂量的生物药物。 AD的强大危险因素是衰老，它与血脑屏障（BBB）的进行性功能障碍相吻合，导致通常被排除在健康大脑中的血清蛋白进入和保留。这些蛋白质之一是白蛋白，在年轻的脑组织中未检测到，而随着年龄的增长而逐渐积聚在大脑中。在这里，我们提出了一种新的策略，用于治疗AD，该策略将利用专辑作为“天然”载体，以增强老年大脑中的siRNA介导的基因靶向。我们假设在静脉内给药后，“搭便车” siRNA上的siRNA将改善老年大脑的siRNA积累和基因沉默活性，从而为与AD相关的靶基因提供了可自定义的策略。在我们的实验室（“ EG18”）中开发的一种新型二酰基脂肪酸载体可以直接连接到siRNA（“ sirna-eg18”），从而促进了这种方法。我们拥有相关的初步数据，表明：1）siRNA-EG18增强了对白蛋白的亲和力和特异性，相对于我们先前发布的Sirna-L2载体，循环半衰期增加； 2）siRNA-EG18在骨关节炎的小鼠模型中施加持续的基因敲低，从而导致白蛋白在发炎的膝关节中积累； 3）静脉注射1 mg/kg剂量静脉注射后24小时，siRNA-EG18在旧但不是年轻小鼠的大脑中积聚。该提案的目标1将通过检查siRNA-EG18的药代动力学，生物分布和毒性作为年龄和给药方案的函数来建立这些结果。 AIM 2将检查老年大脑中siRNA-EG18的生物活性，重点是靶向APOE，APOE是AD的强烈遗传危险因素。总的来说，该建议将建立工作参数，以通过siRNA的白蛋白搭便车在老年大脑中实现基因沉默，从而为AD提供了个性化医学的新机会。