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Hematopoietic stem cell mediated gene therapy for Gaucher disease

造血干细胞介导的戈谢病基因治疗

基本信息

批准号：
09557207
负责人：
SHIMADA Takashi
金额：
$ 7.42万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Gaucher disease, an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase (GC), is an important target for human somatic cell gene therapy. In order to achieve the efficient gene transfer strategy for Gaucher disease, we attempted to optimize the conditions for retroviral mediated gene transfer into hematopoietic stem cells. Approximately 50 % of hematopoietic progenitor cells could be transduced by retroviral vectors using various cytokines, stroma cells, and fibronectin. However, this efficiency is still inadequate for genetic correction of the real hematopoietic stem cells. A major limitation of retroviral vectors appears to be their inability to infect growth arrested cells. To overcome this intrinsic problem, a retroviral vector derived from human immune-deficiency virus (HIV) that is able to infect terminally differentiated cells has been newly developed. We demonstrated that HIV vectors were capable of efficient gene transfer into non-dividing or rarely dividing cells such as hematopoietic cells, neurological cells, and muscle cells. HIV based vectors should be useful for gene therapy of type I Gaucher disease targeting hematopoietic stem cells. We have also shown that bone marrow contains multipotential stem cells that differentiate into neurological cells. Autologous bone marrow cells may be useful as carriers for ex vivo gene therapy for neurological symptoms of type II Gaucher disease.

高谢病是由葡萄糖脑苷酶(GC)缺乏引起的常染色体隐性遗传性溶酶体储存障碍，是人类体细胞基因治疗的重要靶点。为了实现治疗高谢病的有效基因转移策略，我们试图优化逆转录病毒介导的基因转移到造血干细胞的条件。大约50%的造血祖细胞可以通过逆转录病毒载体使用各种细胞因子、基质细胞和纤维连接蛋白进行转导。然而，这种效率仍然不足以对真正的造血干细胞进行遗传纠正。逆转录病毒载体的一个主要局限性似乎是它们无法感染生长受阻的细胞。为了克服这一固有问题，一种来源于人类免疫缺陷病毒(HIV)的逆转录病毒载体被新近开发出来，该载体能够感染终末分化细胞。我们证明了HIV载体能够有效地将基因转移到未分裂或很少分裂的细胞中，如造血细胞、神经细胞和肌肉细胞。基于HIV的载体可用于针对造血干细胞的I型高雪病的基因治疗。我们还发现，骨髓中含有分化为神经细胞的多潜能干细胞。自体骨髓细胞可作为II型高谢病神经症状的体外基因治疗的载体。