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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.

项目总结