Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
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DOI：
10.1126/science.1171242
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发表时间：
2009-11-06
期刊：
影响因子：
56.9
通讯作者：
Aubourg, Patrick
中科院分区：
文献类型：
--
作者：
Cartier, Nathalie;Hacein-Bey-Abina, Salima;Aubourg, Patrick
X连锁肾上腺脑白质营养不良（ALD）是一种发生在男孩身上的严重脑脱髓鞘疾病，由ALD蛋白缺乏引起，ALD蛋白是一种由ABCD1基因编码的三磷酸腺苷结合盒转运体。异基因造血细胞移植（HCT）可阻止ALD病情进展。我们对两名没有匹配供者的ALD患者开展了一项基因治疗试验。从患者体内取出自体CD34(+)细胞，在体外使用编码野生型ABCD1的慢病毒载体进行基因校正，然后在患者接受清髓性治疗后将其重新回输到患者体内。在24到30个月的随访期间，我们检测到多克隆重建，9% - 14%的粒细胞、单核细胞以及T和B淋巴细胞表达ALD蛋白。这些结果有力地表明患者体内的造血干细胞被转导。在回输基因校正细胞后的14到16个月，两名患者的进行性脑脱髓鞘病变停止，这一临床结果与异基因HCT所达到的结果相当。因此，慢病毒介导的造血干细胞基因治疗可在ALD中产生临床益处。
X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34(+) cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.