BONE MARROW GENE THERAPY FOR HURLERS SYNDROME

投掷综合症的骨髓基因疗法

基本信息

批准号：
2713329
负责人：
MEI-MEI HUANG
金额：
$ 3.18万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/2713329
关键词：
O glycosidase bone marrow bone marrow transplantation clinical research disease /disorder model gene expression gene therapy hematopoietic stem cells human subject laboratory mouse microglia mucopolysaccharidosis type I murine leukemia virus transfection transfection /expression vector

项目摘要

Hurler's syndrome is caused by an inherited deficiency of the lysosomal enzyme alpha-L-iduronidase (IDUA). Deficiency of this enzyme can cause accumulation of undigested substrates in the lysosomes and give rise to severe clinical manifestations. Even though allogeneic bone marrow transplantation (BMT) has been applied as a potential treatment, gene therapy, inserting a therapeutic gene into patient's autologous bone marrow cells, may provide similar benefits without causing immunological complications. In this proposed study, IDUA gene transfer into long-lived pluripotent hematopoietic stem cells using retroviral vectors and IDUA gene expression in mature hematopoietic cells will be examined. Possible enzyme delivery into the central nervous system via microglia cells derived from transduced bone marrow will also be analyzed in long-term reconstituted mice. Furthermore, potential immune responses generated in mice transduced by retroviruses carrying human IDUA will be evaluated. This will help to elucidate the possible mechanisms involved in eliminating or silencing cells expressing foreign protein. Information derived from this study will be important for bone marrow gene therapy of Hurler disease and may eventually lead to developing a gene therapy clinical trial protocol for patients.

Hurler's综合征是由溶酶体的遗传缺陷引起的酶α-L-二维醛酸酶（IDUA）。这种酶的不足可能导致溶酶体中未消除的底物的积累并产生严重的临床表现。即使同种异体骨髓移植（BMT）已被用作潜在治疗，基因治疗，将治疗基因插入患者的自体骨骨髓细胞可能会提供类似的好处，而不会引起免疫学并发症。在这项拟议的研究中，IDUA基因转移到长寿使用逆转录病毒载体和IDUA多能造血干细胞将检查成熟造血细胞中的基因表达。可能的酶通过小胶质细胞传递到中枢神经系统从转导的骨髓衍生的也将长期分析重建的小鼠。此外，产生的潜在免疫反应将评估由携带人IDUA转导的逆转录病毒转导的小鼠。这将有助于阐明涉及的可能机制消除表达异物蛋白的或沉默的细胞。信息从这项研究中得出对骨髓基因治疗至关重要投掷疾病，最终可能导致发展基因疗法患者的临床试验方案。