Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells
Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells
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DOI：
10.1172/jci200419205
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发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Naldini, L
中科院分区：
文献类型：
--
作者：
Biffi, A;De Palma, M;Naldini, L
基于基因的递送可以在神经系统内建立治疗性蛋白质的持续供应。对于以广泛的中枢神经系统和周围神经系统（PNS）受累为特征的疾病，可能需要外源基因的广泛分布，这对体内基因转移策略提出了挑战。在这里，我们使用慢病毒载体（LVs），在体外有效地转导了造血干细胞（hsc），并评估了它们的后代靶向治疗基因到移植小鼠的中枢神经系统和PNS的潜力，并纠正神经退行性疾病，异色性白质营养不良（MLD）。我们证实了转基因表达细胞在中枢神经系统小胶质细胞和中枢神经系统神经内膜巨噬细胞中的广泛再生。有趣的是，这些hsc来源的细胞在MLD小鼠中募集更快，更强。通过移植经芳基磺化酶A基因转导的造血干细胞，我们完全重建了MLD小鼠造血系统中的酶活性，并阻止了运动传导障碍、学习和协调缺陷以及该疾病典型的神经病理异常的发展。值得注意的是，离体基因治疗的治疗效果明显高于WT HSC移植，这表明酶过表达在HSC后代中起着关键作用。这些结果表明，移植lv转导的自体造血干细胞是治疗MLD和其他神经退行性疾病的潜在有效策略。
Gene-based delivery can establish a sustained supply of therapeutic proteins within the nervous system. For diseases characterized by extensive CNS and peripheral nervous system (PNS) involvement, widespread distribution of the exogenous gene may be required, a challenge to in vivo gene transfer strategies. Here, using lentiviral vectors (LVs), we efficiently transduced hematopoietic stem cells (HSCs) ex vivo and evaluated the potential of their progeny to target therapeutic genes to the CNS and PNS of transplanted mice and correct a neurodegenerative disorder, metachromatic leukodystrophy (MLD). We proved extensive repopulation of CNS microglia and PNS endoneurial macrophages by transgene-expressing cells. Intriguingly, recruitment of these HSC-derived cells was faster and more robust in MLD mice. By transplanting HSCs transduced with the arylsulfatase A gene, we fully reconstituted enzyme activity in the hematopoietic system of MLD mice and prevented the development of motor conduction impairment, learning and coordination deficits, and neuropathological abnormalities typical of the disease. Remarkably, ex vivo gene therapy had a significantly higher therapeutic impact than WT HSC transplantation, indicating a critical role for enzyme overexpression in the HSC progeny. These results indicate that transplantation of LV-transduced autologous HSCs represents a potentially efficacious therapeutic strategy for MLD and possibly other neurodegenerative disorders.