In Vivo Hematopoietic Stem Cell Transduction.
In Vivo Hematopoietic Stem Cell Transduction.
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DOI：
10.1016/j.hoc.2017.06.001
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Lieber A
中科院分区：
文献类型：
--
作者：
Richter M;Stone D;Miao C;Humbert O;Kiem HP;Papayannopoulou T;Lieber A
目前的造血干细胞基因治疗方法依赖于采集患者的造血干细胞，然后进行体外培养和扩增，使用γ逆转录病毒或慢病毒载体进行修饰，然后将其重新输注到骨髓调节患者体内。虽然这种方法已经成功地应用于许多临床试验，但它依赖于患者HSCs的扩展体外培养也有一系列缺点。在细胞因子的存在下培养HSCs以促进其扩增和转导，被认为对HSCs的长期生存及其归巢和再繁殖能力产生负面影响。重要的是，患者需要清髓方案是一个关键的危险因素，并导致相当大的发病率。除了这些生物学问题外，从后勤和监管的角度来看，体外HSC操作过程也是具有挑战性的，因为操作必须在专门的、经认证的中心进行。这些复杂性导致了这种基因治疗方案的高昂价格，随后严重限制了患者获得这些治疗的机会。体内HSC基因治疗方法旨在通过消除对患者HSCs的体外处理来简化基因治疗过程。体内方法可以细分为三种方法。一种方法是在骨内注射后直接修饰骨髓中的HSCs。另一项涉及静脉注射基因传递载体，这些载体是骨髓中的造血干细胞的归宿。我们开发了另一种方法，将骨髓中的HSCs动员到外周血中，通过静脉载体注射成为基因修饰，然后再移植到骨髓中。我们将提供这三种方法的例子，然后讨论体内HSC基因治疗的优缺点。
Current hematopoietic stem cell (HSC) gene therapy approaches rely on the collection of patient HSCs, followed by their culture and expansion in vitro, their modification using γ-retrovirus or lentiviral vectors, and their re-infusion into myelo-conditioned patients. While this approach has been successfully used in numerous clinical trials, its reliance on the extended ex vivo culture of patient HSCs comes with a set of disadvantages. Culturing HSCs in the presence of a cytokine cocktail to facilitate their expansion and transduction is thought to negatively impact the long-term viability of HSCs, and their homing and repopulation capacity. Importantly, the requirement for myeloablative regimens in patients represents a critical risk factor and results in considerable morbidity. In addition to these biological problems, the process of ex vivo HSC manipulation is also challenging from a logistics and regulatory standpoint, as manipulations must be performed in specialized, accredited centers. These complexities lead to a high price of such gene therapeutic regimens, and subsequently severely limited patient access to these treatments. In vivo HSC gene therapy approaches aim to simplify the gene therapy process by eliminating the need for ex vivo handling of patient HSCs. The in vivo approach can be subdivided into three methods. One method is based on the direct modification of HSCs in the bone marrow following intraosseous injection. Another involves intravenous injection of gene delivery vectors that home to HSCs in bone marrow. We have developed an alternative approach in which HSCs from the bone marrow are mobilized into peripheral blood, become gene modified upon intravenous vector administration, and then re-engraft in the bone marrow. We will provide examples of these three approaches and then discuss the advantages and disadvantages of in vivo HSC gene therapy.
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