Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers

克服细胞外和细胞内屏障的非病毒基因载体的设计

基本信息

  • 批准号:
    8128093
  • 负责人:
  • 金额:
    $ 5.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-29 至 2013-08-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This research proposal is an experimental project that will develop an optimal formulation method for gene therapy in the lungs using non-viral gene carriers. Cystic Fibrosis (CF) is a disease caused by a single-gene defect, which leads to impaired function of the CFTR protein. Although this gene was isolated more than 20 years ago, the development of safe and effective delivery strategies have been difficult to realize. A major limitation in the development of non-viral gene carriers has been the lack of basic understanding of the extracellular and intracellular barriers. For example, it was previously shown that the gene transfer efficiency of gene carriers exposed to mucus lining was dramatically reduced, when compared to mucus-depleted tissues. This is because mucus acts as the primary barrier in the CF lungs, and efficiently removes gene carriers prior to reaching the underlying airway epithelium. To address this, we will determine the rate limiting barriers through human CF mucus and human bronchial epithelial cells for efficient delivery of gene carriers. The approach to this range of studies will be one of systematic building from simple to more complex systems, with an emphasis on quantitative studies at each step. The specific aims of this proposal are: (1) to formulate methods that produce gene carriers that are stable in CF mucus. (2) to determine and quantify gene carrier transport through human CF mucus; (3) to determine intracellular barriers to efficient gene carrier transport to the nucleus in human bronchial epithelial cells; and (4) to determine in vivo gene transfer efficiencies and nasal potential differences (NPD) in mice. We hypothesize that the identification of important extra- and intracellular barriers will guide the rational modification of the non-viral gene carriers for successful CF gene therapy. PUBLIC HEALTH RELEVANCE: Cystic Fibrosis (CF) is a disease caused by a single-gene defect, which leads to impaired function of the CFTR protein responsible for chloride ion transport. Although this gene was isolated more than 20 years ago, the development of safe and effective delivery strategies have been difficult to realize. A major limitation in the development of effective non-viral gene therapy has been the lack of basic understanding of the extracellular and intracellular barriers. We hypothesize that the identification of important rate-limiting barriers will guide the rational modification of the non-viral gene carriers for successful CF gene therapy.
描述(由申请人提供):本研究提案是一项实验项目,将开发一种使用非病毒基因载体进行肺部基因治疗的最佳制剂方法。囊性纤维化(CF)是由单基因缺陷引起的疾病,其导致CFTR蛋白的功能受损。尽管该基因在20多年前就被分离出来,但安全有效的递送策略的开发一直难以实现。在非病毒基因载体的发展中的一个主要限制是缺乏对细胞外和细胞内屏障的基本理解。例如,先前显示,与粘液耗尽的组织相比,暴露于粘液衬里的基因载体的基因转移效率显著降低。这是因为粘液在CF肺中充当主要屏障,并且在到达下面的气道上皮之前有效地去除基因载体。 为了解决这个问题,我们将确定通过人CF粘液和人支气管上皮细胞的限速屏障,以有效递送基因载体。这一系列研究的方法将是从简单到更复杂系统的系统构建,重点是每一步的定量研究。该提案的具体目的是:(1)制定生产在CF粘液中稳定的基因载体的方法。(2)测定和定量基因载体通过人CF粘液的转运;(3)测定人支气管上皮细胞中基因载体有效转运至细胞核的细胞内屏障;和(4)测定小鼠体内基因转移效率和鼻电位差(NPD)。我们推测,重要的细胞外和细胞内的障碍的识别将指导合理的改造非病毒基因载体成功的CF基因治疗。 公共卫生相关性:囊性纤维化(CF)是由单基因缺陷引起的疾病,其导致负责氯离子转运的CFTR蛋白的功能受损。尽管该基因在20多年前就被分离出来,但安全有效的递送策略的开发一直难以实现。有效的非病毒基因治疗的发展的一个主要限制是缺乏对细胞外和细胞内屏障的基本理解。我们推测,重要的限速障碍的识别将指导合理的改造非病毒基因载体成功的CF基因治疗。

项目成果

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Anthony J. Kim其他文献

Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment
  • DOI:
    10.1016/j.addr.2022.114415
  • 发表时间:
    2022-09-01
  • 期刊:
  • 影响因子:
    17.600
  • 作者:
    Nikhil Pandey;Pavlos Anastasiadis;Christine P. Carney;Pranjali P. Kanvinde;Graeme F. Woodworth;Jeffrey A. Winkles;Anthony J. Kim
  • 通讯作者:
    Anthony J. Kim
Toward the scale-up production of polymeric nanotherapeutics for cancer clinical trials
癌症临床试验的聚合物纳米疗法的扩大生产
  • DOI:
    10.1016/j.nantod.2024.102314
  • 发表时间:
    2024-06-01
  • 期刊:
  • 影响因子:
    10.900
  • 作者:
    Md. Musavvir Mahmud;Nikhil Pandey;Jeffrey A. Winkles;Graeme F. Woodworth;Anthony J. Kim
  • 通讯作者:
    Anthony J. Kim

Anthony J. Kim的其他文献

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{{ truncateString('Anthony J. Kim', 18)}}的其他基金

Novel drug delivery strategies for treatment of breast cancer brain metastases
治疗乳腺癌脑转移的新型药物递送策略
  • 批准号:
    10367645
  • 财政年份:
    2022
  • 资助金额:
    $ 5.84万
  • 项目类别:
Novel drug delivery strategies for treatment of breast cancer brain metastases
治疗乳腺癌脑转移的新型药物递送策略
  • 批准号:
    10655301
  • 财政年份:
    2022
  • 资助金额:
    $ 5.84万
  • 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
  • 批准号:
    10113357
  • 财政年份:
    2018
  • 资助金额:
    $ 5.84万
  • 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
  • 批准号:
    10772405
  • 财政年份:
    2018
  • 资助金额:
    $ 5.84万
  • 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
  • 批准号:
    10341155
  • 财政年份:
    2018
  • 资助金额:
    $ 5.84万
  • 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
  • 批准号:
    8679868
  • 财政年份:
    2014
  • 资助金额:
    $ 5.84万
  • 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
  • 批准号:
    9134759
  • 财政年份:
    2014
  • 资助金额:
    $ 5.84万
  • 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
  • 批准号:
    8921999
  • 财政年份:
    2014
  • 资助金额:
    $ 5.84万
  • 项目类别:
Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers
克服细胞外和细胞内屏障的非病毒基因载体的设计
  • 批准号:
    8329751
  • 财政年份:
    2011
  • 资助金额:
    $ 5.84万
  • 项目类别:

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