Catalytic Nanotherapies to Treat Lung Disease

治疗肺部疾病的催化纳米疗法

• 批准号: 9977246
• 负责人: Khalid S Salaita
• 金额: $ 38.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977246
• 关键词: Address; Adrenal Cortex Hormones; Adult; Affect; Allergens; Animal Model; Antibodies; Antisense Technology; Asthma; Binding; Biological; Catalytic DNA; Cells; Characteristics; Chemicals; Chronic; Cleaved cell; Clinic; Clinical; Coupled; Cytoplasm; DNA; DNA Modification Process; Data; Disease; Engineering; Enzymes; Epigenetic Process; Epithelial Cells; Flow Cytometry; Foundations; GATA3 gene; Gene Expression Regulation; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Histology; House Dust Mite Allergens; Human; In Vitro; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Lung; Lung diseases; Mediating; Messenger RNA; Methods; Microscopy; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Myocardial Infarction; Myocardium; Natural Immunity; Oligonucleotides; Oral; Patients; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Process; Prodrugs; RNA; RNA Interference; Resistance; Resolution; Ribonucleases; Ribose; Small Interfering RNA; Steroids; TNF gene; Therapeutic; Therapeutic Agents; Transcript; Transcription Coactivator; Transfection; Translations; Vertebral column; Work; Zinc Fingers; adaptive immunity; airway hyperresponsiveness; asthma model; asthmatic; asthmatic patient; base; cell type; comparative efficacy; cytokine; design; drug action; drug inhalation; drug mechanism; immunogenicity; improved; in vivo Model; inflammatory lung disease; innovation; interdisciplinary collaboration; knock-down; macrophage; mast cell; methacholine; mouse model; myocardial injury; nanoGold; nanoparticle; nanotherapy; novel therapeutics; public health relevance; receptor expression; response; scavenger receptor; side effect; transcription factor; uptake

Asthma is characterized by airway hyper-responsiveness, inflammation, and dysregulation of innate and adaptive immunity. Interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) are characteristic cytokines upregulated in the type 2 helper T cell (Th2) endotype which is the most common form of asthma Expression of these cytokines is driven, in part, by the zinc-finger transcriptional activator, GATA3, which is expressed in different lung cells, such as mast cells, macrophages, and epithelial cells. Indeed, targeting GATA3 is a promising therapeutic avenue to treat asthmatic patients with the Th2 endotype. Several methods to block GATA3 expression levels by knockdown have been previously investigated, including antisense, siRNA, and DNA enzyme (Dz) based approaches. Among these gene-regulation strategies, Dz-based targeting of GATA3 has shown the greatest promise having passed phase II human trials as a treatment for moderate asthma. The efficacy of Dzs is due to the fact that these molecules are short DNA oligonucleotide that catalytically degrades target mRNA, and thus are more efficient compared to antisense and avoiding the immunogenicity and stability issues of RNAi. Through a highly interdisciplinary collaboration between Dr. Salaita (co-PI) and Dr. Wongtrakool (co-PI), the team has obtained preliminary data showing that GATA3- cleaving DNAzyme nanoparticles (DzNP) are 100-fold more active at cleaving GATA-3 compared to soluble Dzs. Importantly, DzNPs also demonstrate significant efficacy in a Th2 mouse model of asthma. The goal of this proposal is to determine why DzNPs mediate improved efficacy compared to soluble Dzs by elucidating the mechanism of how GATA3-DzNPs differ from Dzs in terms of internalization, cell targeting, and stability. Our premise is that DzNPs are more effective compared to soluble Dzs due to the selective delivery of their payload in scavenger receptor expressing cells, which are upregulated in the Th2 endotype. The long-term goal of this proposal is to pave the way for the rational design of improved treatments of lung disease.

哮喘的特征是呼吸道高反应性、炎症和先天及肾上腺皮质激素调节失调。 适应性免疫。白介素4(IL-4)、白介素5(IL-5)和白介素13(IL-13)是特征 细胞因子在2型辅助T细胞(Th2)内型上调，Th2是最常见的哮喘形式 这些细胞因子的表达部分是由锌指转录激活因子GATA3驱动的，它是 表达于不同的肺细胞，如肥大细胞、巨噬细胞和上皮细胞。事实上，目标是 GATA3是治疗Th2内型哮喘的有效途径。几种方法 通过敲除来阻断GATA3的表达水平已经被研究过了，包括反义， SiRNA和DNA酶(DZ)为基础的方法。在这些基因调控策略中，基于DZ的 靶向GATA3已经显示出最大的希望，已经通过了第二阶段的人体试验，作为一种治疗 中度哮喘。DZS的疗效是由于这些分子是短DNA寡核苷酸 从而比反义核酸更有效，从而避免了 RNAi的免疫原性和稳定性问题。通过博士之间高度跨学科的合作。 Salaita(co-Pi)和Wongtrakool博士(co-Pi)，研究小组已经获得了初步数据，表明GATA3- 切割DNAzyme纳米颗粒(DzNP)在切割GATA-3方面的活性是可溶性的100倍 DZS.重要的是，DzNPs在Th2小鼠哮喘模型中也显示出显著的疗效。的目标是 这项建议是为了确定为什么DzNPs与可溶性DZS相比，介导了更好的疗效 GATA3-DzNPs与DZS在内化、细胞靶向性和稳定性方面的不同机制。 我们的前提是DzNPs比可溶性DZS更有效，因为DzNPs选择性地传递其 清道夫受体表达细胞中的有效载荷，在Th2内型中上调。长期的 这项建议的目的是为合理设计改善肺部疾病的治疗方法铺平道路。