Catalytic Nanotherapies to Treat Lung Disease

治疗肺部疾病的催化纳米疗法

基本信息

批准号：
10227119
负责人：
Khalid S Salaita
金额：
$ 38.18万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10227119
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 chronic inflammatory lung disease comparative efficacy cytokine design drug action drug inhalation drug mechanism immunogenicity improved in vivo Model 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

项目摘要

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.

哮喘的特点是气道高反应性、炎症以及先天和气道失调。适应性免疫。白细胞介素 4 (IL-4)、白细胞介素 5 (IL-5) 和白细胞介素 13 (IL-13) 是其特征 2 型辅助 T 细胞 (Th2) 内型细胞因子上调，这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，GATA3 是在不同的肺细胞中表达，例如肥大细胞、巨噬细胞和上皮细胞。确实，针对 GATA3 是治疗 Th2 内型哮喘患者的一种有前景的治疗途径。几种方法之前已经研究过通过敲低来阻断 GATA3 表达水平，包括反义、基于 siRNA 和 DNA 酶 (Dz) 的方法。在这些基因调控策略中，基于 Dz 的 GATA3 的靶向治疗已通过 II 期人体试验，显示出最大的前景中度哮喘。 Dzs 的功效是由于这些分子是短 DNA 寡核苷酸催化降解目标 mRNA，因此与反义相比更有效，并且避免了 RNAi的免疫原性和稳定性问题。通过博士之间的高度跨学科合作。 Salaita (co-PI) 和 Wongtrakool 博士 (co-PI) 团队已获得初步数据显示 GATA3- 与可溶性 DNAzyme 纳米颗粒 (DzNP) 相比，裂解 GATA-3 的活性高 100 倍 Dzs。重要的是，DzNPs 在 Th2 小鼠哮喘模型中也表现出显着的功效。目标是该提案旨在通过阐明 DzNPs 与可溶性 Dzs 相比为何能提高功效 GATA3-DzNPs 在内化、细胞靶向和稳定性方面与 Dzs 有何不同的机制。我们的前提是，DzNPs 比可溶性 Dzs 更有效，因为它们的选择性传递清道夫受体表达细胞中的有效负载，其在 Th2 内型中上调。长期来看该提案的目标是为合理设计改进肺部疾病治疗方法铺平道路。