New polymeric nanoparticles for Cystic Fibrosis gene therapy

用于囊性纤维化基因治疗的新型聚合物纳米颗粒

• 批准号: 7679451
• 负责人: RAZ JELINEK
• 金额: $ 3.36万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-11-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679451
• 关键词: Adsorption; Adult; Aerosols; Affect; Animals; Attention; Avidity; Base Composition; Breathing; Cell Nucleus; Cells; Charge; Chemicals; Chemistry; Child; Chloride Ion; Collaborations; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Diffusion; Disease; Drug Delivery Systems; Drug Formulations; Dyes; Epithelial Cells; Epithelium; Exhibits; Exposure to; Failure; Fluorescence; Fluorescence Microscopy; Gene Delivery; Gene Expression; Gene Transfer; Generations; Genes; Goals; Head; Heel; Human; In Vitro; Incubated; Individual; Inflammatory Response; Institutes; Ion Transport; Label; Laboratories; Life; Ligands; Lung; Lung diseases; Methods; Modification; Molecular Weight; Mucous body substance; Mus; Nose; Pathway interactions; Penetration; Physiological; Polyethylene Glycols; Process; Property; Research; Research Personnel; Resistance; Single-Gene Defect; Structure of mucous membrane of nose; Surface; Surface Properties; System; Testing; Therapeutic; Thick; Time; Transfection; Universities; Work; base; cystic fibrosis mouse; density; design; extracellular; gene therapy; improved; in vivo; innovation; nanobiotechnology; nanocarrier; nanoparticle; new technology; particle; public health relevance; research study; tool; trafficking; uptake; vector

DESCRIPTION (provided by applicant): Cystic Fibrosis (CF) is a lethal cureless disease affecting more than 30,000 children and adults in the US, caused by a single-gene defect that leads to impaired function of the CFTR protein responsible for chloride ion transport. The pathological hallmark of CF is the formation of thick mucus lining the lung airways, which cannot be promptly cleared by ciliary action. The accumulated mucus obstructs the lungs, makes breathing difficult and promotes bacterial invasion, ultimately eliciting a massive inflammatory response. Furthermore, the mucosal layer, which is the primary extracellular barrier in the CF lung, is a major cause for the failure of varied therapeutic approaches to CF. In particular, the thick mucus has been a critical obstacle for aerosol gene therapy for CF (i.e. delivery of gene vectors through the lung airways rather than intravenously), which generally holds tremendous potential as a therapeutic avenue. The goal of the proposed research is the construction and testing of a new nanoparticle-based platform for CF gene therapy that would facilitate penetration through the lung mucosal barrier, leading to overall higher transfection efficiency. The laboratory of Prof. Justin Hanes, Head of Therapeutics at the Institute of NanoBioTechnology at Johns Hopkins University (the host researcher), has been in the scientific and technological forefront for developing innovative polymeric nanoparticle (NP) carriers for pulmonary therapeutics. Specifically, the primary vehicle pursued in the research will be porous polymeric NPs modulated with polyethylene-glycol (PEG), recently shown in the Hanes laboratory to significantly enhance mucosal permeation. Overall, the proposed work is guided by the hypothesis that a comprehensive and quantitative approach to the development of polymeric NP assemblies exhibiting enhanced penetration through mucosal barriers is essential, and indeed possible, for successful CF gene therapy. The conceptual and technological advances pursued in the proposed project could open the way for varied therapeutic avenues for pulmonary diseases and targeted drug delivery through physiological aerial pathways. PUBLIC HEALTH RELEVANCE: The proposed research aims to develop an innovative gene therapy approach for cystic fibrosis, a cureless lethal lung disease often leading to considerable human suffering. The research will focus on a new technology for effective delivery of "gene nano-carriers" through the thick mucus barrier in CF lungs.

描述（由申请人提供）：囊性纤维化（CF）是一种致命的无法治愈的疾病，在美国影响超过30，000名儿童和成人，由单基因缺陷引起，导致负责氯离子转运的CFTR蛋白功能受损。CF的病理学标志是形成厚的粘液衬在肺气道中，其不能通过纤毛作用迅速清除。积聚的粘液阻塞肺部，使呼吸困难，促进细菌入侵，最终引发大规模的炎症反应。此外，作为CF肺中的主要细胞外屏障的粘膜层是CF的各种治疗方法失败的主要原因。特别是，粘稠的粘液一直是CF气溶胶基因治疗（即通过肺气道而不是静脉内递送基因载体）的关键障碍，其通常具有作为治疗途径的巨大潜力。拟议研究的目标是构建和测试一种新的基于纳米颗粒的CF基因治疗平台，该平台将有助于穿透肺粘膜屏障，从而提高整体转染效率。约翰霍普金斯大学纳米生物技术研究所治疗学负责人Justin Hanes教授的实验室（主持研究员）一直处于开发用于肺部治疗的创新聚合物纳米颗粒（NP）载体的科学和技术前沿。具体而言，在研究中追求的主要载体将是用聚乙二醇（PEG）调制的多孔聚合物NP，最近在Hanes实验室中显示出显著增强粘膜渗透。总的来说，所提出的工作是由一个全面的和定量的方法来发展的聚合物NP组件表现出增强的渗透通过粘膜屏障是必不可少的，而且确实可能的，成功的CF基因治疗的假设指导。在拟议项目中追求的概念和技术进步可以为肺部疾病的各种治疗途径和通过生理空中途径的靶向药物输送开辟道路。公共卫生相关性：这项研究的目的是开发一种创新的基因治疗方法来治疗囊性纤维化，囊性纤维化是一种无法治愈的致命性肺部疾病，通常会导致相当大的人类痛苦。这项研究将集中在一种新技术上，通过CF肺中厚厚的粘液屏障有效地输送“基因纳米载体”。