Delivery of Sleeping Beauty Transposons to Dog Liver for Gene Therapy

将睡美人转座子输送到狗肝脏进行基因治疗

基本信息

  • 批准号:
    7537339
  • 负责人:
  • 金额:
    $ 29.09万
  • 依托单位:
  • 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:
    2008-08-15 至 2011-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The overall goal of Discovery Genomics, Inc. is to develop the Sleeping Beauty transposon system for human gene therapy. To achieve this to treat hemophilia, we must be able to direct uptake and long-term expression of therapeutic genes in targeted tissues such as the liver. Only one method of plasmid delivery has been effective for high-level gene expression in the liver in mice - the rapid, high-pressure delivery known as hydrodynamic injection. In the mouse, hydrodynamic delivery of DNA requires injection of a large volume (10% vol/wt) of a DNA solution through the tail vein in less than 10 seconds. For larger animals, this procedure is conjectured to be unacceptable on a whole animal basis. In this highly focused project we propose to develop catheter-based, local hydrodynamic delivery to the liver of dogs that will require minimal surgery and amounts of therapeutic DNA. These features are especially important for the delivery of Factor IX and Factor VIII-expressing transposons for treatment of hemophilia. Recognizing that delivery to only one cell type in the liver (and other organs) is not possible, we will to couple physical and biological controls over gene expression to our transgenic constructs that will reduce their expression in hematopoietic cells to reduce undesirable immunological responses. This project will dovetail with our ongoing SBIR project to deliver Factor VIII and IX genes in dogs via open-chest surgery for treatment of hemophilia. The Specific Aims of the project are to 1) develop appropriate transposons with reporter genes and recovery cassettes that can be used to evaluate the efficacy of hydrodynamic delivery in dogs, 2) determine an optimal, catheter-based delivery procedure that can be used to inject DNA with minimal surgical intervention into canine livers, and 3) demonstrate that long-term gene expression will result from transposition of Sleeping Beauty transposons into canine hepatocytes using the procedure(s) developed in Aim 2. Public Health Relevance: Delivery of Sleeping Beauty Transposons to Dog Liver for Gene Therapy. There currently is no efficient and effective method for delivery of Sleeping Beauty transposons to liver in humans for gene therapy. The goal of this project is to develop a transposon delivery system that will allow hydrodynamic delivery of SB transposons in dogs as a model large animal for humans.
描述(由申请人提供):Discovery Genomics,Inc.是开发用于人类基因治疗的睡美人转座子系统。为了实现这一点来治疗血友病,我们必须能够在靶组织(如肝脏)中直接摄取和长期表达治疗基因。只有一种质粒递送方法对小鼠肝脏中的高水平基因表达有效-快速高压递送,即流体动力学注射。在小鼠中,DNA的流体动力学递送需要在小于10秒内通过尾静脉注射大体积(10%vol/wt)的DNA溶液。对于较大的动物,该程序在整个动物基础上是不可接受的。在这个高度集中的项目中,我们建议开发基于导管的局部流体动力学递送到狗的肝脏,这将需要最少的手术和治疗DNA的量。这些特征对于用于治疗血友病的因子IX和因子VIII表达转座子的递送尤其重要。认识到在肝脏(和其他器官)中仅递送到一种细胞类型是不可能的,我们将对基因表达进行物理和生物控制与我们的转基因构建体偶联,所述转基因构建体将减少它们在造血细胞中的表达以减少不期望的免疫应答。该项目将与我们正在进行的SBIR项目相吻合,该项目通过开胸手术在狗中递送因子VIII和IX基因以治疗血友病。该项目的具体目标是:1)开发具有报告基因和回收盒的适当转座子,可用于评估犬中流体动力学递送的功效,2)确定最佳的基于导管的递送程序,可用于以最小的手术干预将DNA注射到犬肝脏中,和3)证明了使用目的2中开发的方法将睡美人转座子转座到犬肝细胞中将导致长期基因表达。 公共卫生相关性:将睡美人转座子输送到狗肝进行基因治疗。 目前还没有将睡美人转座子递送至人类肝脏用于基因治疗的有效且高效的方法。该项目的目标是开发一种转座子递送系统,该系统将允许将SB转座子在作为人类模型大动物的狗中进行流体动力学递送。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting DNA With Fingers and TALENs.
DDE transposases: Structural similarity and diversity.
  • DOI:
    10.1016/j.addr.2010.06.006
  • 发表时间:
    2010-09-30
  • 期刊:
  • 影响因子:
    16.1
  • 作者:
    Nesmelova, Irina V.;Hackett, Perry B.
  • 通讯作者:
    Hackett, Perry B.
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PERRY B. HACKETT其他文献

PERRY B. HACKETT的其他文献

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{{ truncateString('PERRY B. HACKETT', 18)}}的其他基金

SB Transposons for Gene Therapy
用于基因治疗的 SB 转座子
  • 批准号:
    8277315
  • 财政年份:
    2010
  • 资助金额:
    $ 29.09万
  • 项目类别:
SB Transposons for Gene Therapy
用于基因治疗的 SB 转座子
  • 批准号:
    7886257
  • 财政年份:
    2010
  • 资助金额:
    $ 29.09万
  • 项目类别:
SB Transposons for Gene Therapy
用于基因治疗的 SB 转座子
  • 批准号:
    8053259
  • 财政年份:
    2010
  • 资助金额:
    $ 29.09万
  • 项目类别:
SB Transposons for Gene Therapy
用于基因治疗的 SB 转座子
  • 批准号:
    8464380
  • 财政年份:
    2010
  • 资助金额:
    $ 29.09万
  • 项目类别:
Targeted Transposons for Gene Therapy
用于基因治疗的靶向转座子
  • 批准号:
    7274374
  • 财政年份:
    2007
  • 资助金额:
    $ 29.09万
  • 项目类别:
Sleeping beauty transposon for gene therapy
用于基因治疗的睡美人转座子
  • 批准号:
    6861185
  • 财政年份:
    2004
  • 资助金额:
    $ 29.09万
  • 项目类别:
Transposon-mediated Gene Therapy for Fanconi Anemia
转座子介导的范可尼贫血基因治疗
  • 批准号:
    6787819
  • 财政年份:
    2004
  • 资助金额:
    $ 29.09万
  • 项目类别:
Sleeping Beauty-Mediated Gene Therapy for Hemophilia A
睡美人介导的 A 型血友病基因治疗
  • 批准号:
    6582681
  • 财政年份:
    2003
  • 资助金额:
    $ 29.09万
  • 项目类别:
Sleeping Beauty-Mediated Gene Therapy for Hemophilia
睡美人介导的血友病基因治疗
  • 批准号:
    6883402
  • 财政年份:
    2003
  • 资助金额:
    $ 29.09万
  • 项目类别:
SLEEPING BEAUTY TRANSPOSON FOR GENE THERAPY
用于基因治疗的睡美人转座子
  • 批准号:
    6442591
  • 财政年份:
    2001
  • 资助金额:
    $ 29.09万
  • 项目类别:

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