DNA Nanostructures as siRNA Delivery Vehicles for Alzheimer's Therapy

项目总结/摘要 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，其特征在于 认知能力逐渐退化。目前可用的AD治疗是对症药物 旨在改善认知和行为症状，而不改变疾病的潜在过程， 减缓疾病进展。因此，需要针对AD的改善疾病的治疗策略， 可以阻断或改变导致神经变性的分子病理步骤。RNA干扰是一种 这种策略已经被积极地用于选择性敲低AD靶基因，但通常使用 病毒载体具有制备和安全性问题。 我们提出了一种新的DNA纳米技术方法来克服这些问题。DNA纳米技术提供 对建筑形状和结构的近原子控制，消除了药物载体尺寸的不均匀性。DNA 可以用另外的化学基团官能化，所述化学基团允许药物分子的可控连接， 保护药物免受生物降解。由于DNA是一种生物材料，DNA纳米结构引发了 当用于药物递送时，最小的免疫应答是无毒的、生物相容的和可生物降解的。 此外，DNA纳米结构可以在不需要转染剂的情况下进入细胞。我们的方法将使用 DNA多面体作为基于RNA干扰的AD治疗的模型结构。具体而言，我们将：（1） 开发具有可控的小干扰RNA（siRNA）附着的DNA多面体，并掺入2 '-O- 甲基链，以增强在生理环境中的生物稳定性，和（2）建立DNA的活力 在人诱导多能干细胞（iPSC）衍生的AD模型细胞系中基于纳米结构的药物递送。 我们的建议汇集了一个跨学科的团队，包括化学研究人员的不同群体， 生物学和神经系统疾病提供了一种新的方法用于RNAi治疗AD。拟议 该策略具有许多优点，包括（i）精确的药物装载和定量，（i）生物相容性 和生物降解性，（iii）低剂量高功效，和（iv）增强的生物稳定性，以承受 生理条件和复杂的生物流体。我们预计，我们的方法将提供一个强有力的证据， 通过DNA纳米结构进行可行的siRNA递送的概念，在AD的临床治疗中具有巨大的未来潜力。

Project Summary/Abstract 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, (i) 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.