病毒载体与造血干细胞基因治疗

Development of Gene Therapy for Hematopoietic Stem Cell Using Viral Vectors

多种获得性和遗传性疾病累及造血细胞。造血干细胞是人类基因治疗的重要靶细胞。成功的造血干细胞基因治疗不仅需要高效基因转移 ,还需要治疗基因的长期、高水平表达。反转录病毒载体是造血干细胞基因治疗的常用载体 ,结合优化的造血干细胞转导条件 ,其介导的腺苷脱氨酶缺陷引起的严重联合免疫缺陷和X染色体连锁的严重联合免疫缺陷的基因治疗已经获得初步成功 ;其他整合型病毒载体如慢病毒和腺相关病毒载体 ,也在临床前造血干细胞基因治疗研究中得到广泛应用。从病毒载体。

Hematopoietic stem cells (HSC) are attractive targets for gene therapy of inherited and acquired disorders in hematopoietic system in that they possess the properties of self renewal,proliferation,and multi lineage differentiation.For successful gene therapy,the viral vector mediated gene addition strategy has two essential prerequisites:1) the efficient transfer of therapeutic gene into HSC;2) the long term and stable expression of the transgene at therapeutic levels.The oncoretrovirus derived vectors are best understood and most widely investigated.Recent successful cases of gene therapy for severe combined immunodeficiency due to adenosine deaminase or γ c chain deficiencies have provided strong evidences that retrovirus mediated gene transfer into HSC will work in clinical treatment.While these results are encouraging,some obstacles remain to be circumvented including low efficiency of gene transfer and gene silencing in retroviral vector system.The therapeutic gene can be efficiently introduced into HSC by HIV 1 based lentiviral vector due to its capability to infect the quiescent cells.A variety of preclinical studies are now conducted and a number of valuable results highlight the efficacy of lentiviral mediated gene transfer into HSC.However,the potential value of lentival vectors in human gene therapy remains to be demonstrated.Adeno associated virus vector is an alternative to retroviral and lentiviral vectors.This review summarizes the characteristics of integrating vectors,the improved HSC transduction protocols,and the optimized gene expression strategies and outlines the important advances of preclinical and clinical trials in hematopoietic stem cell gene therapy.