Catalytic Nanotherapies to Treat Lung Disease

治疗肺部疾病的催化纳米疗法

• 批准号: 10169812
• 负责人: Khalid S Salaita
• 金额: $ 5.74万
• 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/10169812
• 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.

哮喘的特征在于气道高反应性、炎症和先天性和先天性哮喘的调节异常。 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）是特征性的 在2型辅助性T细胞（Th 2）内型中上调的细胞因子是最常见的哮喘形式 这些细胞因子的表达部分由锌指转录激活因子GATA 3驱动， 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。事实上， GATA 3是治疗Th 2型哮喘患者的一种有前途的治疗途径。几种方法 通过敲低阻断GATA 3表达水平的方法，包括反义， siRNA和基于DNA酶（Dz）的方法。在这些基因调控策略中，基于Dz的 靶向GATA 3已经显示出最大的希望，已经通过了II期人体试验，作为治疗 中度哮喘Dzs的功效是由于这些分子是短的DNA寡核苷酸 其催化降解靶mRNA，因此与反义相比更有效，并避免了 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），该团队已经获得了初步数据，显示GATA 3- 切割DNA酶纳米颗粒（DzNP）在切割加塔-3方面的活性是可溶性DNA酶纳米颗粒（DzNP）的100倍。 Dzs。重要的是，DzNP还在哮喘的Th 2小鼠模型中显示出显著的功效。的目标 该建议是通过阐明以下内容来确定DzNP与可溶性Dz相比介导改善的功效的原因： GATA 3-DzNPs在内化、细胞靶向和稳定性方面与Dzs不同的机制。 我们的前提是DzNP与可溶性Dz相比更有效，这是由于它们的选择性递送。 有效载荷在清道夫受体表达细胞中，其在Th 2内型中上调。长期 该提案的目的是为合理设计改进的肺部疾病治疗方法铺平道路。