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.

项目概要 虽然许多组织，包括但不限于大型制药公司，都使用纳米技术来制定 治疗性核酸（TNA）的递送，批准用于临床的概念数量屈指可数。 造成这种情况的主要原因是普遍缺乏对其至关重要的 TNA 特性的了解。 最近，有多家美国生物技术公司发布新闻稿。 一些患者因严重炎症反应（细胞因子风暴）而放弃 TNA。 的公司转向使用合理设计的核酸的更复杂的配方 （纳米TNA） 显然，新型纳米TNA的免疫毒性和免疫调节作用是明显的。 很大程度上未知，必须对其进行定义才能将这项技术成功转化为临床。 该项目将向科学界通报纳米 TNA 的免疫原性，并提供调整指南 它们的理化特性，以避免不良的免疫副作用。 提议研究纳米 TNA 的免疫原性并提出其成功的策略 根据我们之前的工作数据和初步结果，我们过渡到治疗应用。 伪造纳米 TNA 的免疫原性可以通过改变其相对大小、电荷、 为了测试这个创新假设，我们在这个项目中寻求 R01 机制的支持。 Afonin 博士（北卡罗来纳大学夏洛特分校）和 Khisamutdinov 博士（鲍尔州立大学）实验室将生成一组 纳米 TNA 并概括地描述了它们的特征。 小组将协助研究和分析纳米 TNA 引发的免疫反应，其目标是 确定免疫和血液相容性方面的结构-活性关系 (SAR)。 克莱姆森大学实验室将协助 Tropsha 博士进行进一步详细的纳米 TNA 体内研究。 （北卡罗来纳大学教堂山分校）将根据获得的数据协助开发预测计算模型 实验数据以及生物数据与纳米 TNA 理化性质的相关性。 这项前沿的跨学科工作将提高对纳米 TNA SAR 的理解，并将引领 我们将致力于开发纳米​​ TNA 平台以实现更广泛的生物医学应用。 通过数据库服务器公开提供，其中包含所有已知纳米 TNA 的详细资料。 该提案的完成将引导我们开发高效的下一代纳米 TNA 平台，而该平台缺乏 该研究的长期目标是提高纳米免疫原性和高治疗潜力。 TNA 达到临床使用水平。