RIG-I Activating Nanoparticles for Immunopotentiation

用于免疫增强的 RIG-I 激活纳米颗粒

• 批准号: 10709018
• 负责人: Anna Marie Pyle
• 金额: $ 59.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709018
• 关键词: Address; Affinity; Agonist; Antiviral Agents; Artificial nanoparticles; Beds; Behavior; Biodistribution; Biological; Charge; Chemicals; Clinical; Cytosol; Data; Development; Disease; Double-Stranded RNA; Drug Delivery Systems; Drug Kinetics; Endosomes; Engineering; Foundations; Generations; Genes; Half-Life; Hydrophobicity; Immune Targeting; Immune checkpoint inhibitor; Immunobiology; Immunologics; Immunosuppression; Immunotherapeutic agent; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interdisciplinary Study; Interferon Type I; Investigation; Knowledge; Lead; Length; Libraries; Modality; Modeling; Molecular; Mus; Natural Immunity; Oligonucleotides; Organism; Outcome; Pathway interactions; Pattern recognition receptor; Pharmacologic Substance; Phosphorylation; Polymer Chemistry; Polymers; Positioning Attribute; Predisposition; Property; RNA; Research; Safety; Science; Site; Structure; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transfection; Translations; Tretinoin; Tumor Immunity; Vaccine Adjuvant; Viral; Virus Diseases; adaptive immunity; antitumor effect; cancer immunotherapeutics; cancer immunotherapy; clinical application; combinatorial; cytotoxicity; design; drug development; efficacy evaluation; immune activation; immunogenic; immunogenicity; improved; in vivo; in vivo evaluation; innovation; insight; lead candidate; melanoma; mouse model; multidisciplinary; nanocarrier; nanomedicine; nanoparticle; nanopolymer; new technology; next generation; novel; nuclease; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; preclinical development; preclinical evaluation; prevent; programs; response; stem; synergism; technology platform; therapeutic RNA; tumor; tumor growth; tumor microenvironment; uptake

PROJECT SUMMARY The innate immune system can be pharmacologically programed to elicit desired immunological outcomes. Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that has emerged as a promising innate immune target for immunopotentiation. RIG-I is activated upon recognizing 5’-triphosphorylated, double- stranded RNA (3pRNA) in the cytosol, which stimulates an antiviral-like inflammatory program that can be harnessed to treat or prevent a diversity of diseases. However, the potency and efficacy of 3pRNA has been limited by major drug delivery barriers, including nuclease degradation, inefficient cellular uptake and cytosolic delivery, and rapid clearance. To address these challenges, we have developed RIG-I activating nanoparticles (RANs). RANs are polymer nanoparticles that are engineered to promote the cytosolic delivery of synthetic, molecularly-defined, and high-affinity stem-loop RNA (SLR) RIG-I agonists recently developed by our team. The objective of this R01 application is to optimize and advance RANs as a versatile platform for pharmacological activation of RIG-I. We will accomplish this through the following Specific Aims. First, we will engineer next-generation RANs with improved properties for systemic administration through optimization of SLR and polymer charge and hydrophobicity. This approach will leverage combinatorial chemical diversity to access a new design space for 3pRNA delivery, which we expect will yield next-generation RANs with higher SLR loading efficiency, reduced cytotoxicity, protection from nuclease degradation, improved stability, and enhanced immunostimulatory activity. Second, we will establish relationships between RAN properties, innate immune activation, pharmacokinetics, polymer and SLR biodistribution, and toxicity. These studies are essential in the preclinical development of new immunotherapeutic modalities and will also yield new insight into how nanocarriers can be engineered for safe and effective activation of RIG-I. We expect these studies to yield next-generation RANs that are optimized for systemic administration of SLR therapeutics. Third, while RANs have broad potential clinical applications, we will evaluate their efficacy as a systemically administered cancer immunotherapy in poorly immunogenic mouse models of melanoma as a clinically important test case. We expect to demonstrate that systemic administration of lead-candidate RANs will activate RIG-I in the tumor microenvironment, resulting in an immunological reprograming of tumor sites that inhibits tumor growth and synergizes with immune checkpoint inhibitors. Collectively, these studies will position RANs as an enabling platform for immunopotentiation with potential to address the significant need for new cancer immunotherapies, antiviral agents, and vaccine adjuvants.

项目摘要 可以通过药物编程的先天免疫系统来引起所需的免疫学结果。 视黄酸诱导的基因I（rig-i）是一种模式识别受体，已成为有望先天的受体 免疫目标的免疫靶标。识别5'三磷酸化，双重 - 滞留的RNA（3PRNA）在细胞质中，刺激可以是抗病毒样炎症程序 利用以治疗或预防多样化的疾病。 但是，3PRNA的效力和效率已经 受主要药物输送障碍的限制，包括核酸酶降解，效率低下的细胞摄取和胞质效果 交付和快速许可。为了应对这些挑战，我们开发了RIG-I激活纳米颗粒 （兰斯）。兰斯是聚合物纳米颗粒，用于促进合成的胞质递送， 我们团队最近开发的分子定义，高亲和力的茎环RNA（SLR）RIG-1激动剂。 该R01应用程序的目的是优化和预付票作为多功能平台 RIG-I的药理激活。我们将通过以下特定目标来实现这一目标。首先，我们会的 通过优化 SLR和聚合物电荷和疏水性。这种方法将利用组合化学多样性 访问3PRNA交付的新设计空间，我们期望这将产生下一代的运输量 SLR载荷效率，降低细胞毒性，免受核酸酶降解的保护，提高稳定性和 增强的免疫刺激活性。其次，我们将建立RAN属性，先天性之间的关系 免疫激活，药代动力学，聚合物和SLR生物分布和毒性。这些研究是 在新的免疫治疗方式的临床前开发中至关重要，还将产生新的见解 如何设计纳米载体以安全有效地激活RIG-I。我们希望这些研究能够 产生的下一代命令已针对SLR治疗的全身服用进行了优化。第三，而 租金具有广泛的潜在临床应用，我们将评估它们作为系统管理的有效性 黑色素瘤的免疫原性小鼠模型中的癌症免疫疗法是临床上重要的测试用例。 我们希望证明铅候选租金的全身施用将激活肿瘤中的RIG-I 微环境，导致肿瘤部位的免疫重编程，抑制肿瘤生长和 与免疫检查点抑制剂协同作用。总的来说，这些研究将把命中率定位为 免疫量的平台，有潜力解决新的癌症免疫疗法的重要需求， 抗病毒药和疫苗调节器。