Characterization of various multifunctional nucleic acid nanoparticles and understanding their immunotoxicity

各种多功能核酸纳米粒子的表征并了解其免疫毒性

• 批准号: 9384048
• 负责人: Kirill A Afonin
• 金额: $ 35.99万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384048
• 关键词: Address; Adverse effects; Antisense Oligonucleotides; Biodistribution; Biological; Biotechnology; Blood; Cells; Charge; Clinic; Clinical; Clinical Trials; Communities; Computer Simulation; DNA; Data; Data Correlations; Databases; Development; Disease; Drops; Drug Delivery Systems; Engineering; Fluorescent Dyes; Formulation; Generations; Genes; Goals; Hepatotoxicity; Hydrophobicity; Immune response; Immunologics; Immunologist; In Vitro; Inflammatory; Injection of therapeutic agent; Laboratories; Lead; Lipids; Liposomes; Liver; MicroRNAs; Molecular; Nanostructures; Nanotechnology; Nucleic Acids; Organ; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Press Releases; Property; Quantitative Structure-Activity Relationship; RNA; Reaction; Research; Research Project Grants; Role; Shapes; Small Interfering RNA; Specialist; Structure-Activity Relationship; Surface; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Thermodynamics; Tissues; Translations; Universities; Work; aerobic respiration control protein; aptamer; base; chemical property; chemical stability; cheminformatics; cytokine; design; immunogenicity; immunoregulation; immunotoxicity; improved; in vivo; innovation; knock-down; nanodevice; nanomaterials; nanomedicine; nanoparticle; nanotherapeutic; next generation; novel; nucleic acid structure; programs; small molecule; targeted delivery; therapeutic development; therapeutic miRNA

PROJECT SUMMARY While many organizations, including but not limited to big pharma, use nanotechnology to formulate the delivery of therapeutic nucleic acids (TNA), the number of concepts approved for clinical use is only a handful. The major reason for this is the general lack of understanding of TNA properties critical for their immunocompatibility. Recently, there have been press releases announcing several US biotech companies dropping TNAs due to severe inflammatory reactions (cytokine storm) in patients. To address the issue, some of the companies switched to more sophisticated formulations that employ rationally designed nucleic acids (nano-TNAs). It is evident that the immunotoxicity and immunomodulatory effects of new nano-TNAs are largely unknown and must be defined to permit successful translation of this technology into the clinic. This project will inform the scientific community about immunogenicity of nano-TNAs and provide a guide for tuning their physicochemical properties to avoid undesirable immunological side effects. The current application proposes to investigate the immunogenicity of nano-TNAs and to propose a strategy for their successful transition to therapeutic applications. Based on the data from our previous work and preliminary results, we hypothesized that the immunogenicity of nano-TNAs can be controlled by changing their relative size, charge, shape and composition. To test this innovative hypothesis, we seek R01 mechanism support. In this project, Drs. Afonin’s (UNC Charlotte) and Khisamutdinov’s (Ball State University) laboratories will generate a panel of nano-TNAs and extensively characterize them. Drs. Marriott’s (UNC Charlotte) and Dobrovolskaia’s (NCL) groups will assist in studies and analysis of the immunological responses triggered by nano-TNAs with the goal of determining the structure-activity relationship (SAR) in terms of immuno- and hemato-compatibility. Dr. Lee’s laboratory, at Clemson University, will assist with further detailed in vivo studies of nano-TNAs. Dr. Tropsha (UNC Chapel Hill) will assist in development of predictive computational models based on the obtained experimental data and correlation of biological data to physicochemical properties of nano-TNAs. The results of this cutting-edge, interdisciplinary work will improve the understanding of SAR for nano-TNAs and will lead to the development of nano-TNA platforms for broader biomedical applications. We will make our results publically available via database server that will feature detailed profiles of all known nano-TNAs. Ultimately, completion of this proposal will lead us to development of efficient next generation nano-TNA platforms lacking immunogenicity and featuring high therapeutic potential. The long term goal of this study is to elevate nano- TNAs to the level of clinical use.

项目摘要 虽然许多组织，包括但不限于大型制药公司，使用纳米技术来制定 在治疗性核酸（TNA）的递送方面，批准用于临床使用的概念的数量仅为少数。 其主要原因是人们普遍缺乏对TNA特性的了解， 免疫相容性最近，有新闻稿宣布，几家美国生物技术公司 由于患者的严重炎症反应（细胞因子风暴）而导致TNA下降。为了解决这个问题，一些 的公司转而使用更复杂的配方， （纳米TNA）。很明显，新的纳米TNAs的免疫毒性和免疫调节作用是显著的。 很大程度上是未知的，并且必须被定义以允许将该技术成功地转化为临床。这 该项目将向科学界通报纳米TNA的免疫原性，并为调整提供指导 它们的物理化学性质以避免不希望的免疫副作用。当前应用程序 建议研究纳米TNAs的免疫原性，并提出一种成功的策略， 过渡到治疗应用。根据我们以前工作的数据和初步结果，我们 假设纳米-TNAs的免疫原性可以通过改变它们的相对大小，电荷， 形状和组成。为了验证这一创新假设，我们寻求R 01机制的支持。在这个项目中， Drs. Afonin的（夏洛特夏洛特）和Khisamutdinov的（鲍尔州立大学）实验室将产生一个小组， nano-TNAs和广泛表征它们。Drs. Marriott's（夏洛特夏洛特）和Dobrovolskaia's（NCL） 小组将协助研究和分析纳米TNA引发的免疫反应， 确定免疫和血液相容性方面的构效关系（SAR）。李博士的 在克莱姆森大学的一个实验室，将协助进一步详细的纳米TNA体内研究。特罗普莎医生 (UNC查佩尔山）将协助开发预测计算模型， 实验数据和生物学数据与纳米TNA的物理化学性质的相关性。结果 这项尖端的跨学科工作将提高对纳米TNA SAR的理解，并将导致 纳米TNA平台的发展，更广泛的生物医学应用。我们会让我们的结果 可通过数据库服务器获得，该服务器将提供所有已知纳米TNA的详细配置文件。最后， 完成这项建议将导致我们开发有效的下一代纳米TNA平台缺乏 免疫原性和具有高治疗潜力。这项研究的长期目标是提高纳米 TNA达到临床使用水平。