Hematopoietic stem cell mediated gene therapy for Gaucher disease

造血干细胞介导的戈谢病基因治疗

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-09557207/
• 关键词: Gene Therapy; Viral vectors; Gaucher disease; Hematopoietic stem cells; Gaucher病; レトロウィルスベクター; AAVベクター; Gancher病; 骨髄ストローマ細胞; フィブロネクチン

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.

Gaucher病是由缺乏葡萄糖核苷酶（GC）引起的一种常染色体隐性溶酶体储存障碍，是人类体细胞基因疗法的重要靶标。为了实现高ch氏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中的条件。使用各种细胞因子，基质细胞和纤连蛋白的逆转录病毒载体可以转导约50％的造血祖细胞。但是，这种效率仍然不足以对真实造血干细胞的遗传校正。逆转录病毒载体的主要局限似乎是它们无法感染生长被捕的细胞。为了克服这个内在的问题，源自人免疫缺陷病毒（HIV）的逆转录病毒载体已被新开发。我们证明了HIV载体能够有效地转移到非分裂或很少分裂的细胞中，例如造血细胞，神经系统细胞和肌肉细胞。基于艾滋病毒的载体应对靶向造血干细胞的I型高刺病的基因治疗有用。我们还表明，骨髓包含分化为神经细胞的多稳态干细胞。自体骨髓细胞可作为II型Gaucher病神经系统症状的离体基因治疗的载体。

项目成果

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