New polymeric nanoparticles for Cystic Fibrosis gene therapy

描述(申请人提供)：囊性纤维化(CF)是一种致命的无法治愈的疾病，在美国影响着30,000多名儿童和成年人，由单基因缺陷引起，导致负责氯离子运输的CFTR蛋白功能受损。CF的病理特征是肺内形成厚厚的粘液，这种粘液不能通过纤毛作用迅速清除。累积的粘液阻塞肺部，使呼吸困难，促进细菌入侵，最终引发大规模炎症反应。此外，粘膜层是CF肺的主要细胞外屏障，也是各种治疗方法失败的主要原因。特别是，厚厚的粘液一直是CF气雾化基因治疗的关键障碍(即通过肺部呼吸道而不是静脉输送基因载体)，这通常具有巨大的治疗潜力。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，该平台将促进透过肺粘膜屏障，从而导致整体更高的转染率。约翰霍普金斯大学纳米生物技术研究所治疗学主任贾斯汀·哈内斯教授的实验室(东道主研究员)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。具体地说，研究中追求的主要载体将是由聚乙二醇(PEG)调制的多孔性聚合物纳米颗粒，最近在Hanes实验室显示，它可以显著增强粘膜渗透。总体而言，建议的工作是以这样一个假设为指导的，即开发能够增强透过粘膜屏障的聚合物NP组件的全面和定量方法对于成功的CF基因治疗是必要的，而且确实是可能的。拟议项目中追求的概念和技术进步可为肺部疾病的各种治疗途径和通过生理性空中路径定向药物输送开辟道路。公共卫生相关性：拟议的研究旨在为囊性纤维化开发一种创新的基因治疗方法，囊性纤维化是一种无法治愈的致命肺部疾病，通常会导致相当大的人类痛苦。这项研究将专注于一种新的技术，通过CFF肺内厚厚的粘液屏障有效地传递“基因纳米载体”。

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.