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

基本信息

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
项目类别：
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

项目摘要

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) 是一种无法治愈的致命疾病，影响美国 30,000 多名儿童和成人，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的病理特征是肺气道内壁形成厚厚的粘液，不能通过纤毛作用及时清除。积累的粘液会阻塞肺部，使呼吸困难并促进细菌入侵，最终引发大规模炎症反应。此外，粘膜层是CF肺中主要的细胞外屏障，是各种CF治疗方法失败的主要原因。特别是，浓稠的粘液一直是 CF 气雾剂基因治疗（即通过肺气道而不是静脉内输送基因载体）的关键障碍，而气雾剂基因治疗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基于纳米颗粒的新 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（主持研究员）的实验室在开发用于肺部治疗的创新聚合物纳米颗粒 (NP) 载体方面一直处于科技前沿。具体来说，该研究的主要载体将是用聚乙二醇（PEG）调制的多孔聚合物纳米颗粒，哈内斯实验室最近证明其可显着增强粘膜渗透性。总体而言，拟议的工作以这样的假设为指导：对于成功的 CF 基因治疗来说，采用全面、定量的方法来开发具有增强的粘膜屏障渗透性的聚合物 NP 组装体是必不可少的，而且实际上是可能的。拟议项目中所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路径进行靶向药物输送开辟道路。公共健康相关性：拟议的研究旨在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。该研究将重点关注一种新技术，用于通过 CF 肺部厚厚的粘液屏障有效输送“基因纳米载体”。