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: 10013239
• 负责人: Kirill A Afonin
• 金额: $ 34.83万
• 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/10013239
• 关键词: Address; Antisense Oligonucleotides; Biodistribution; Biological; Biotechnology; Blood; Cells; Charge; Clinic; Clinical; Clinical Trials; Communities; Computer Models; 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; Injections; 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; 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 release syndrome; design; immunogenicity; immunoregulation; immunotoxicity; improved; in vivo; innovation; knock-down; nanodevice; nanomaterials; nanomedicine; nanoparticle; nanotherapeutic; next generation; novel; nucleic acid structure; nucleic acid-based therapeutics; programs; side effect; 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。 免疫相容性。近期，不断有新闻稿宣布多家美国生物科技公司 由于患者严重炎症反应（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 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。这 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。当前应用 提议研究纳米 TNA 的免疫原性并提出其成功的策略 过渡到治疗应用。根据我们之前工作的数据和初步结果，我们 假设纳米 TNA 的免疫原性可以通过改变其相对大小、电荷、 形状和组成。为了检验这一创新假设，我们寻求 R01 机制的支持。在这个项目中， 博士。 Afonin（北卡罗来纳大学夏洛特分校）和 Khisamutdinov（鲍尔州立大学）实验室将生成一组 纳米 TNA 并对其进行广泛表征。博士。万豪酒店 (UNC 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，其目标是 确定免疫和血液相容性方面的结构活性关系（SAR）。李博士的 克莱姆森大学实验室将协助进一步详细的纳米 TNA 体内研究。特罗普沙博士 （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。结果 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 开发纳米 TNA 平台以实现更广泛的生物医学应用。我们将做出我们的成果 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。最终， 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 具有免疫原性和高治疗潜力。这项研究的长期目标是提高纳米 TNA 达到临床使用水平。