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

• 批准号: 10418236
• 负责人: Arun Richard Chandrasekaran
• 金额: $ 31.24万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 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/10418236
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Award; Behavior; Behavioral Symptoms; Biocompatible Materials; Biological; Biological Assay; Biology; Cell Line; Cell Survival; Cells; Chemicals; Chemistry; Cholinesterase Inhibitors; Clinical Treatment; Cognition; Collaborations; Complex; Custom; DNA; DNA delivery; Data; Deposition; Deterioration; Development; Disease; Disease Progression; Disease model; Drug Carriers; Drug Delivery Systems; Environment; Face; Funding; Funding Opportunities; Future; Gene Silencing; Genes; Grant; Heterogeneity; Human; Immune response; Institutes; Measures; MicroRNAs; Modeling; Modification; Molecular; Mutation; N-Methyl-D-Aspartate Receptors; Nanostructures; Nanotechnology; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Neurotransmitters; Pathologic; Persons; Pharmaceutical Preparations; Physiological; Pilot Projects; Preparation; Publishing; RNA Interference; RNA Interference Therapy; Research; Research Personnel; Safety; Senile Plaques; Shapes; Small Interfering RNA; Structure; System; Technology; Therapeutic Human Experimentation; Therapeutic Uses; Toxic effect; Training; Transfection; Treatment Efficacy; Viral Vector; age related neurodegeneration; antagonist; base; biomaterial compatibility; brain tissue; chemical group; cognitive capacity; delivery vehicle; design; dosage; immunogenic; immunogenicity; improved; induced pluripotent stem cell; innovation; interest; knock-down; mRNA Expression; nerve stem cell; nervous system disorder; novel; novel strategies; presenilin-1; protein aggregation; protein expression; screening; self assembly; side effect; symptom treatment; tau Proteins; treatment strategy; uptake

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.

项目摘要/摘要 阿尔茨海默氏病（AD）是最常见的与年龄相关的神经退行性疾病，其特征是 逐步确定认知能力。目前的广告治疗方法是有症状的代理 旨在改善认知和行为症状，而不会改变疾病的潜在过程或 疾病进展减慢。这是有必要为AD改组疾病的治疗策略 可以阻止或修改导致神经退行性的分子病理步骤。 RNA干扰是一个 积极采用的这种策略以选择性敲除广告目标基因的选择性，但通常使用 病毒向量有准备和安全问题。 我们提出了一种新的DNA纳米技术方法来克服这些问题。 DNA纳米技术提供 对建筑形状和结构的近乎原子控制，消除了药物载体大小的异质性。脱氧核糖核酸 可以与其他化学基团功能化，以控制药物分子的附着 保护该药物免受生物降解。由于DNA是一种生物材料，因此DNA纳米结构会引起 在药物输送中使用时，最小的免疫激发是无毒的，生物相容性的和可生物降解的。 此外，DNA纳米结构可以进入细胞，而无需转染剂。我们的方法将使用 DNA多面体作为基于RNA干扰的AD的模型结构。具体来说，我们将：（1） 开发带有小干扰RNA（siRNA）的DNA Polyhedra，并掺入2'-O- 甲基链以增强物理环境的生物稳定性，（2）建立DNA的生存能力 人类诱导多能干细胞（IPSC）衍生的AD模型细胞系中的基于纳米结构的药物递送。 我们的建议将一个跨学科团队汇集在一起​​，完成了一群化学研究人员的研究人员， 生物学和神经系统疾病为RNAi治疗AD提供了新的方法。提议 策略具有许多优点，包括（i）精确的药物加载和数量，（i）生物相容性 和生物降解性，（iii）高效率的低剂量，（iv）增强的生物稳定性可承受 生理条件和复杂的生物流体。我们预计我们的方法将提供强大的证明 DNA纳米结构的可行siRNA递送的概念，具有巨大的AD临床治疗潜力。