Sleeping Beauty-Mediated Gene Therapy for Hemophilia A
睡美人介导的 A 型血友病基因治疗
基本信息
- 批准号:6582681
- 负责人:
- 金额:$ 14.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-02-01 至 2003-10-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Hemophilia A is a bleeding disorder caused by the absence of clotting factor VIII (FVIII). This disease is inherited in an X-linked recessive manner and it is estimated that there are 15,000 affected individuals in the U.S. Treatment of Hemophilia A has been greatly improved over the last 10 years with the availability of recombinant FVIII (recombinate). However, the high expense of this treatment (as much as $100,000 per year in severe cases) and variable levels of FVIII maintained in the circulation compromise the effectiveness of this therapy. FVIII gene therapy presents a therapeutic alternative for hemophilia A, which would provide more consistent levels of circulating FVIII and thus more efficacious and cost-effective treatment of the disease. Here the investigators propose development of the Sleeping Beauty (SB) transposon system for non-viral FVIII gene transfer and expression in the liver as a therapeutic approach for hemophilia A. The approach is based on the studies that demonstrate long-term, SB transposon-mediated gene expression in the liver and lung. It is hypothesized that the FVIII gene can similarly be delivered to the liver of experimental animals, providing long-term and curative expression of human FVIII. Two Specific Aims are proposed to address this prediction. In SPECIFIC AIM 1, several SB transposons will be assembled which are designed to introduce and express the human FVIII gene under transcriptional regulation of several different strong promoters. Constructs that contain both transposon and transposase functions on the same plasmid will be made. FVlll transposition and expression functions will first be tested in cultured human cells (HEK 293 and Huh7 hepatoma). In SPECIFIC AIM 2, the FVIII transposon constructs tested in Aim 1 will be introduced into the livers of FVIII-deficient knock-out mice by intravenous administration, subsequently testing these animals for long-term expression of FVIII in the circulation with improved clotting of tested blood and decreased bleeding. Results from these experiments will support subsequent scale-up and translation of the Sleeping Beauty transposase system for treatment of hemophilia A, to be proposed as part of a phase II SBIR study.
Technological Innovation: Sleeping Beauty is a novel gene transfer system with potential application in gene therapy. The market size for the inherited-diseases market niche, to which this technology applies, is about to $5.8 billion
描述(由申请方提供):血友病A是一种由凝血因子VIII(FVIII)缺乏引起的出血性疾病。这种疾病以X连锁隐性方式遗传,据估计,美国有15,000名受影响的个体。在过去10年中,随着重组FVIII(重组)的可用性,血友病A的治疗得到了极大的改善。然而,这种治疗的高费用(在严重病例中每年高达100,000美元)和在循环中维持的可变水平的FVIII损害了这种疗法的有效性。FVIII基因治疗为血友病A提供了一种治疗替代方案,它将提供更一致的循环FVIII水平,从而更有效和更具成本效益的疾病治疗。在这里,研究人员建议开发睡美人(SB)转座子系统,用于在肝脏中进行非病毒FVIII基因转移和表达,作为血友病A的治疗方法。该方法是基于研究表明,长期,SB转座子介导的基因表达在肝脏和肺。假设FVIII基因可以类似地递送至实验动物的肝脏,提供人FVIII的长期和治愈性表达。提出了两个具体目标来解决这一预测。在SPECIFIC AIM 1中,将组装几个SB转座子,这些转座子旨在在几个不同强启动子的转录调节下引入和表达人FVII基因。将制备在同一质粒上含有转座子和转座酶功能的构建体。将首先在培养的人细胞(HEK 293和Huh7肝细胞瘤)中测试FVIII转座和表达功能。在特定目的2中,目的1中测试的FVIII转座子构建体将通过静脉内给药引入FVIII缺陷型敲除小鼠的肝脏中,随后测试这些动物在循环中FVIII的长期表达,并改善测试血液的凝固和减少出血。这些实验的结果将支持用于治疗血友病A的睡美人转座酶系统的后续放大和翻译,作为II期SBIR研究的一部分。
技术创新:睡美人是一种新型的基因转移系统,在基因治疗中具有潜在的应用前景。这项技术所适用的遗传疾病市场利基的市场规模约为58亿美元
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets.
- DOI:10.1016/j.chembiol.2009.02.010
- 发表时间:2009-04-24
- 期刊:
- 影响因子:0
- 作者:Kalén M;Wallgard E;Asker N;Nasevicius A;Athley E;Billgren E;Larson JD;Wadman SA;Norseng E;Clark KJ;He L;Karlsson-Lindahl L;Häger AK;Weber H;Augustin H;Samuelsson T;Kemmet CK;Utesch CM;Essner JJ;Hackett PB;Hellström M
- 通讯作者:Hellström M
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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
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
- 批准号:
7537339 - 财政年份:2008
- 资助金额:
$ 14.51万 - 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:
$ 14.51万 - 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:
$ 14.51万 - 项目类别:
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