Catalytic Nanotherapies to Treat Lung Disease

治疗肺部疾病的催化纳米疗法

• 批准号: 10463234
• 负责人: Khalid S Salaita
• 金额: $ 6.2万
• 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/10463234
• 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

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.

哮喘的特点是气道的高反应性、炎症和先天和

项目成果

"Turbo-Charged" DNA Motors with Optimized Sequence Enable Single-Molecule Nucleic Acid Sensing.

具有优化序列的“涡轮增压”DNA 电机可实现单分子核酸传感。

• DOI: 10.1002/anie.202316851
• 发表时间: 2024
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Zhang,Luona;Piranej,Selma;Namazi,Arshiya;Narum,Steven;Salaita,Khalid
• 通讯作者: Salaita,Khalid

Nanodiscoidal Nucleic Acids for Gene Regulation.

• DOI: 10.1021/acschembio.3c00038
• 发表时间: 2023-11-17
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Sharma, Radhika;Narum, Steven;Liu, Shuhong;Dong, Yixiao;Baek, Kyung In;Jo, Hanjoong;Salaita, Khalid
• 通讯作者: Salaita, Khalid

Gene Regulation Using Nanodiscs Modified with HIF-1-α Antisense Oligonucleotides.

• DOI: 10.1021/acs.bioconjchem.1c00505
• 发表时间: 2022-02-16
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Sharma R;Dong Y;Hu Y;Ma VP;Salaita K
• 通讯作者: Salaita K