DNA Nanostructures as siRNA Delivery Vehicles for Alzheimer's Therapy

DNA 纳米结构作为 siRNA 递送载体用于治疗阿尔茨海默病

基本信息

批准号：
10725478
负责人：
Arun Richard Chandrasekaran
金额：
$ 11.24万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
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：
2022-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725478
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease therapy Behavioral Symptoms Biocompatible Materials Biological Biology Cell Line Cells Chemistry Clinical Treatment Complex DNA DNA delivery Deterioration Disease Disease Progression Drug Carriers Drug Delivery Systems Environment Future Genes Heterogeneity Human Immune response Modeling Molecular Nanostructures Nanotechnology Nerve Degeneration Neurobehavioral Manifestations Pathologic Pharmaceutical Preparations Physiological Preparation RNA Interference Research Personnel Safety Shapes Small Interfering RNA Structure System Toxic effect Transfection Viral Vector age related neurodegeneration biomaterial compatibility chemical group cognitive capacity delivery vehicle dosage improved induced pluripotent stem cell interest knock-down nervous system disorder novel strategies side effect treatment strategy

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, characterized by progressive deterioration of cognitive capacity. Currently available treatments for AD are symptomatic agents that aim to improve cognitive and behavioral symptoms without altering the underlying course of the disease or slowing disease progression. Thus, there is a necessity for disease-modifying treatment strategies for AD that can block or modify the molecular pathological steps leading to neurodegeneration. RNA interference is one such strategy that has been actively pursued for selective knockdown of AD target genes, but typically used viral vectors have preparation and safety concerns. We propose a new DNA nanotechnology approach to overcome these issues. DNA nanotechnology offers near- atomic control over building shapes and structures, eliminating heterogeneity in size of drug carriers. DNA can be functionalized with additional chemical groups that allow controllable attachment of drug molecules and protect the drug against biological degradation. Since DNA is a biological material, DNA nanostructures elicit minimal immune response when used in drug delivery, are non-toxic, biocompatible and biodegradable. Further, DNA nanostructures can enter cells without the need for a transfection agent. Our approach will use DNA polyhedra as model structures for RNA interference based treatment of AD. Specifically, we will: (1) develop DNA polyhedra with controllable attachment of small interfering RNAs (siRNAs) and incorporate 2'-O-methyl strands to enhance biostability in physiological environments, and (2) establish viability of DNA nanostructure- based drug delivery in human induced pluripotent stem cell (iPSC) derived AD model cell lines. Our proposal brings together an interdisciplinary team comprising a diverse group of researchers in chemistry, biology, and neurological disorders to provide a novel approach for RNAi treatment of AD. The proposed strategy has a number of advantages including (i) precise drug loading and quantification, (ii) biocompatibility and biodegradability, (iii) low dosage with high efficacy, and (iv) enhanced biostability to withstand physiological conditions and complex biofluids. We anticipate that our approach will provide a robust proof of concept for viable siRNA delivery by DNA nanostructures with great future potential for clinical treatment of AD.

项目概要阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病，其特征是目前可用的 AD 治疗方法是对症治疗。旨在改善认知和行为症状而不改变疾病的根本病程或因此，有必要针对 AD 采取疾病缓解治疗策略。可以阻断或改变导致神经退行性变的分子病理步骤，RNA干扰就是其中之一。这种策略已被积极追求选择性敲低 AD 靶基因，但通常使用病毒载体有准备和安全问题。我们提出了一种新的 DNA 纳米技术方法来克服这些问题。原子控制构建形状和结构，消除药物载体 DNA 大小的异质性。用额外的化学基团进行功能化，允许药物分子的可控附着，并且保护药物免遭生物降解由于 DNA 是一种生物材料，DNA 纳米结构会引发化学反应。用于药物输送时免疫反应最小，无毒、生物相容性和可生物降解。 DNA 纳米结构无需转染剂即可进入细胞。我们的方法将使用 DNA。具体来说，我们将：（1）开发多面体作为基于 RNA 干扰的 AD 治疗的模型结构。 DNA 多面体，可控制附着小干扰 RNA (siRNA) 并掺入 2'-O-甲基链以增强生理环境中的生物稳定性，以及（2）建立 DNA 纳米结构的可行性- 基于人诱导多能干细胞 (iPSC) 衍生的 AD 模型细胞系的药物递送。我们的提案汇集了一个跨学科团队，由化学领域的不同研究人员组成，生物学和神经系统疾病为RNAi治疗AD提供了一种新的策略。具有许多优点，包括（i）精确的载药量和定量，（ii）生物相容性和生物降解性，（iii）低剂量高效，以及（iv）增强的生物稳定性以承受生理我们预计我们的方法将为可行的概念提供强有力的证明。通过 DNA 纳米结构传递 siRNA 在 AD 临床治疗方面具有巨大的未来潜力。