IDURONIDASE GENE TRANSFER INTO HEMATOPOIETIC CELLS
艾杜糖醛酸酶基因转移至造血细胞
基本信息
- 批准号:6647728
- 负责人:
- 金额:$ 30.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-09-30 至 2005-02-28
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Metabolic storage disease like mucopolysaccharidosis can potentially be cured by ex vivo transfer of the deficient gene into autologous hematopoietic stem cells followed by infusion of the genetically corrected cells. Transduction efficiency into hematopoietic stem cells of large animals and humans though has been too low to achieve a therapeutic effect. In this proposal, we wish to evaluate strategies with low toxicity to increase engraftment of hematopoietic stem cells transduced with Moloney murine leukemia virus (MoMLV) vectors transduced marrow cells in the absence of conditioning or infusions after partial marrow ablation with either hydroxyurea, methotrexate or busulfan are at least as effective as 200 cGy TBI, shown to be more effective in our past studies. Another hurdle towards gene therapy is the possible induction of immune responses to transduced cells and the transgene encoded proteins. We propose to characterize the immune response in normal beagles to autologous marrow cells transduced with the "foreign" human IDU gene to correlate the long-term persistence of these transduced cells with the host's immune response. We wish to develop methods to prevent or decrease this response by immunosuppressive treatment after transplantation. The most effective method will be tested in IDU-deficient dogs which will receive autologous marrow cells transduced with the "foreign" canine IDU gene followed by immunosuppressive treatment. Hematopoietic stem cells are considered to be predominantly quiescent. Gene transfer into hematopoietic stem cells by MoMLV vectors is not efficient in part due to their inability to transduce non-dividing cells. As human immunodeficiency virus type 1 (HIV-1) based vectors have been shown to infect non-dividing target cells, we wish to compare the efficiency of HIV-1 vectors containing the canine IDU gene with corresponding MoMLV vectors to transduce stem cells of normal and IDU deficient dogs. The outlined studies will address current problems of gene transfer and, if successful, will facilitate future gene therapy of Hurler syndrome and other diseases.
代谢性储存疾病,如粘多糖症,可以通过在体外将缺陷基因转移到自体造血干细胞中,然后输注经过基因校正的细胞来治愈。然而,在大型动物和人类的造血干细胞中的转导效率太低,无法达到治疗效果。在这项建议中,我们希望评估低毒的策略,在未经处理或部分骨髓切除后用羟基脲、甲氨蝶呤或丁硫丹输注的情况下,增加由Moloney小鼠白血病病毒(MoMLV)载体转导的造血干细胞的植入至少与200cGyTBI一样有效,这在我们过去的研究中被证明是更有效的。基因治疗的另一个障碍是可能诱导对转导细胞和转基因编码蛋白的免疫反应。我们建议对正常比格犬对转导“外来”人类IDU基因的自体骨髓细胞的免疫反应进行表征,以将这些转导细胞的长期存续期与宿主的免疫反应联系起来。我们希望通过移植后的免疫抑制治疗来预防或减少这种反应。最有效的方法将在IDU缺陷的狗身上进行测试,这些狗将接受转导“外来”犬IDU基因的自体骨髓细胞,然后进行免疫抑制治疗。造血干细胞被认为主要是静止的。通过MoMLV载体将基因转移到造血干细胞是无效的,部分原因是它们不能转导未分裂的细胞。由于人类免疫缺陷病毒1型(HIV-1)载体已被证明可以感染未分裂的靶细胞,我们希望比较含有犬IDU基因的HIV-1载体和相应的MoMLV载体转导正常和IDU缺陷犬干细胞的效率。概述的研究将解决目前的基因转移问题,如果成功,将促进未来赫勒综合征和其他疾病的基因治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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FRIEDRICH G SCHUENING其他文献
FRIEDRICH G SCHUENING的其他文献
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{{ truncateString('FRIEDRICH G SCHUENING', 18)}}的其他基金
PHASE II TRIAL EXAMINING MULTIPLE IV INFUSIONS OF FOUR DOSES OF ABX C
II 期试验检查四剂 ABX C 的多次 IV 输注
- 批准号:
6568823 - 财政年份:2001
- 资助金额:
$ 30.14万 - 项目类别:
PHASE II TRIAL EXAMINING MULTIPLE IV INFUSIONS OF FOUR DOSES OF ABX C
II 期试验检查四剂 ABX C 的多次 IV 输注
- 批准号:
6468946 - 财政年份:2000
- 资助金额:
$ 30.14万 - 项目类别:
PHASE II TRIAL EXAMINING MULTIPLE IV INFUSIONS OF FOUR DOSES OF ABX C
II 期试验检查四剂 ABX C 的多次 IV 输注
- 批准号:
6411629 - 财政年份:2000
- 资助金额:
$ 30.14万 - 项目类别:
PHASE II TRIAL EXAMINING MULTIPLE IV INFUSIONS OF FOUR DOSES OF ABX C
II 期试验检查四剂 ABX C 的多次 IV 输注
- 批准号:
6265738 - 财政年份:1998
- 资助金额:
$ 30.14万 - 项目类别:
IDURONIDASE GENE TRANSFER INTO HEMATOPOIETIC CELLS
艾杜糖醛酸酶基因转移至造血细胞
- 批准号:
6177077 - 财政年份:1994
- 资助金额:
$ 30.14万 - 项目类别:
HUMAN GC GENE TRANSDUCTION INTO HEMATOPOIETIC CELLS
人类 GC 基因转导至造血细胞
- 批准号:
2148441 - 财政年份:1994
- 资助金额:
$ 30.14万 - 项目类别:
IDURONIDASE GENE TRANSFER INTO HEMATOPOIETIC CELLS
艾杜糖醛酸酶基因转移至造血细胞
- 批准号:
2843549 - 财政年份:1994
- 资助金额:
$ 30.14万 - 项目类别:
IDURONIDASE GENE TRANSFER INTO HEMATOPOIETIC CELLS
艾杜糖醛酸酶基因转移至造血细胞
- 批准号:
6915315 - 财政年份:1994
- 资助金额:
$ 30.14万 - 项目类别:
HUMAN GC GENE TRANSDUCTION INTO HEMATOPOIETIC CELLS
人类 GC 基因转导至造血细胞
- 批准号:
2148439 - 财政年份:1994
- 资助金额:
$ 30.14万 - 项目类别: