Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I
Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I
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DOI：
10.1007/s10545-017-0052-4
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发表时间：
2017-07-01
影响因子：
4.2
通讯作者：
Aiuti, Alessandro
中科院分区：
文献类型：
--
作者：
Penati, Rachele;Fumagalli, Francesca;Aiuti, Alessandro
溶酶体贮积病（LSD）是一种罕见的遗传性代谢紊乱，其特征是溶酶体功能障碍，导致废物积累和严重的器官损伤。酶替代疗法（ERT）和造血干细胞移植（HSCT）已被开发为LSD的潜在治疗方法，但临床前和临床研究显示，在某些情况下，疗效有限。静脉ERT能控制内脏器官损害，但不能预防神经损害。根据疾病类型，HSCT在对早期变异进行治疗时具有重要的局限性，除非在疾病发作前进行治疗。在试图克服这些问题的过程中，已经提出基因治疗作为一种有价值的治疗选择，或者离体，用体外遗传修饰的靶细胞，或者体内，通过全身或实质内原位施用插入遗传物质。特别地，使用用含有突变基因的健康拷贝的病毒载体转导的自体造血干细胞（HSC）将允许缺陷酶的超正常生产和多个组织（包括中枢神经系统）中靶细胞的交叉校正。本文综述了基于HSC的基因治疗LSD的最新科学进展，特别关注异染性脑白质营养不良（MLD）和粘多糖样变性I型（MPS-I）。
Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset. In the attempt to overcome these issues, gene therapy has been proposed as a valuable therapeutic option, either ex vivo, with target cells genetically modified in vitro, or in vivo, by inserting the genetic material with systemic or intra-parenchymal, in situ administration. In particular, the use of autologous haematopoietic stem cells (HSC) transduced with a viral vector containing a healthy copy of the mutated gene would allow supra-normal production of the defective enzyme and cross correction of target cells in multiple tissues, including the central nervous system. This review will provide an overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I).