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
基本信息
- 批准号:9384048
- 负责人:
- 金额:$ 35.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdverse effectsAntisense OligonucleotidesBiodistributionBiologicalBiotechnologyBloodCellsChargeClinicClinicalClinical TrialsCommunitiesComputer SimulationDNADataData CorrelationsDatabasesDevelopmentDiseaseDropsDrug Delivery SystemsEngineeringFluorescent DyesFormulationGenerationsGenesGoalsHepatotoxicityHydrophobicityImmune responseImmunologicsImmunologistIn VitroInflammatoryInjection of therapeutic agentLaboratoriesLeadLipidsLiposomesLiverMicroRNAsMolecularNanostructuresNanotechnologyNucleic AcidsOrganPatientsPharmaceutical PreparationsPharmacologic SubstancePolymersPress ReleasesPropertyQuantitative Structure-Activity RelationshipRNAReactionResearchResearch Project GrantsRoleShapesSmall Interfering RNASpecialistStructure-Activity RelationshipSurfaceTechniquesTechnologyTestingTherapeuticTherapeutic EffectThermodynamicsTissuesTranslationsUniversitiesWorkaerobic respiration control proteinaptamerbasechemical propertychemical stabilitycheminformaticscytokinedesignimmunogenicityimmunoregulationimmunotoxicityimprovedin vivoinnovationknock-downnanodevicenanomaterialsnanomedicinenanoparticlenanotherapeuticnext generationnovelnucleic acid structureprogramssmall moleculetargeted deliverytherapeutic developmenttherapeutic miRNA
项目摘要
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.
项目总结
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
在提供治疗性核酸(TNA)方面,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TNA属性的了解,这些属性对其
免疫兼容性。最近,有新闻稿宣布了几家美国生物科技公司
患者因严重炎症反应(细胞因子风暴)而降低TNAS。为了解决这个问题,一些
的公司转而使用更复杂的配方,使用合理设计的核酸
(Nano-TNAS)。显然,新的纳米TNAs的免疫毒性和免疫调节作用是
这在很大程度上是未知的,必须加以定义,才能将这项技术成功地转化为临床。这
该项目将向科学界通报纳米TNAs的免疫原性,并为调整提供指南
它们的物理化学性质,以避免不良的免疫副作用。当前应用程序
建议研究纳米TNAs的免疫原性,并提出其成功的策略
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,
形状和构图。为了检验这一创新假说,我们寻求R01机制的支持。在这个项目中,
阿弗宁博士(北卡罗来纳大学夏洛特分校)和基萨穆迪诺夫博士(鲍尔州立大学)的实验室将产生一个小组
并对其进行广泛的表征。Marriott博士(北卡罗来纳大学夏洛特分校)和Dobrovolskaia博士(NCL)
小组将协助研究和分析纳米TNA引发的免疫反应,目标是
从免疫和血液相容性的角度确定构效关系(SAR)。李博士的
克莱姆森大学的实验室将协助进一步详细的体内纳米TNAs研究。特罗普莎博士
(北卡罗来纳州教堂山分校)将协助开发基于所获得的预测计算模型
实验数据和生物数据与纳米TNA的物理化学性质的关联。结果是
这一前沿、跨学科的工作将提高对SAR对纳米TNA的理解,并将引领
为更广泛的生物医学应用开发纳米TNA平台。我们会取得我们的成绩
通过数据库服务器向公众提供,该数据库将提供所有已知纳米TNA的详细概况。最终,
这项提案的完成将使我们开发出高效的下一代纳米TNA平台
免疫原性,具有很高的治疗潜力。这项研究的长期目标是提升纳米级的
达到临床应用的水平。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kirill A Afonin其他文献
Kirill A Afonin的其他文献
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{{ truncateString('Kirill A Afonin', 18)}}的其他基金
Multiplexed electronic counting of scarce protein targets using nucleic acid nanoparticles
使用核酸纳米粒子对稀有蛋白质靶标进行多重电子计数
- 批准号:
10353490 - 财政年份:2022
- 资助金额:
$ 35.99万 - 项目类别:
Multiplexed electronic counting of scarce protein targets using nucleic acid nanoparticles
使用核酸纳米粒子对稀有蛋白质靶标进行多重电子计数
- 批准号:
10611370 - 财政年份:2022
- 资助金额:
$ 35.99万 - 项目类别:
SMART NANPs: new molecular platform for communication with human immune system and modulation of therapeutic responses
SMART NANP:与人体免疫系统通讯和调节治疗反应的新分子平台
- 批准号:
10331771 - 财政年份:2021
- 资助金额:
$ 35.99万 - 项目类别:
SMART NANPs: new molecular platform for communication with human immune system and modulation of therapeutic responses
SMART NANP:与人体免疫系统通讯和调节治疗反应的新分子平台
- 批准号:
10557793 - 财政年份:2021
- 资助金额:
$ 35.99万 - 项目类别:
Administrative Supplement to SMART NANPs: new molecular platform for communication with human immune system and modulation of therapeutic responses
SMART NANP 的行政补充:用于与人体免疫系统沟通和调节治疗反应的新分子平台
- 批准号:
10798083 - 财政年份:2021
- 资助金额:
$ 35.99万 - 项目类别:
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 - 财政年份:2017
- 资助金额:
$ 35.99万 - 项目类别:
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