Gene therapy for human severe combined immunodeficiencies
Gene therapy for human severe combined immunodeficiencies
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DOI：
10.1016/s1074-7613(01)00175-3
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发表时间：
2001-07-01
期刊：
影响因子：
32.4
通讯作者：
Cavazzana-Calvo, M
中科院分区：
文献类型：
--
作者：
Fischer, A;Hacein-Bey, S;Cavazzana-Calvo, M
这些局限性在塞夫勒芸香街149号现在已经克服了。在最近法国巴黎发表的几篇综述中详细讨论了这一领域的进展（Halene和Kohn，2000; Sadelain等人，2000;威廉姆斯和史密斯，2000;坎多蒂，2000）。已设计包装细胞系以产生高滴度的逆转录病毒颗粒，而假型化原则上，基因治疗对于具有来自猴或猫逆转录病毒遗传的血液传播疾病的包膜的病毒是有吸引力的选择，因为基因转移到病毒中显著增加了具有自我更新能力的造血干细胞（HSC）-CD 34（+）造血前体细胞的转导速率（Kelly等人，它应该导致治愈。此外，虽然仍然很差2000）。在离体感染阶段，使用细胞表征的HSC可以容易地以相对因子（即，flt 3-配体、干细胞因子（SCF））和骨髓中的大量细胞或通过有核细胞分化因子（MGDF）中的动员来回收，使细胞分裂，从而物理上可用于基因转移。视力早期造血无分化但有几项临床试验基于基因转移祖细胞。用纤连蛋白将培养袋包被到造血细胞中不会导致有效的转片段（CH 296），也会增加这些细胞的转导速率（综述于Candotti，2000）。通过将细胞和病毒颗粒聚集在一起（Hanenberg临床级批准的载体使基因整合等，1996年）的报告。最后，通过将所有沉默序列修剪到造血细胞基因组中或引入绝缘子来修饰载体可以来自小鼠肿瘤逆转录病毒。此类载体增强转基因转录速率。考虑到这些进展被发现在小鼠计数的转导中是有效的，比较HSC的结果是不合适的，但比较人HSC的结果更不合适（米勒，1992）。最近进行的临床试验中，这两个因素解释了这种差异。人类HSC形成较早。表达少量的膜受体，
149 Rue de Sevres of these limitations have now been overcome. Progress in this area is discussed in detail in several recently 75015 Paris France published reviews (Halene and Kohn, 2000; Sadelain et al., 2000; Williams and Smith, 2000; Candotti, 2000). Packaging cell lines have been designed to produce a high titer of retroviral particles, while pseudotyping ofIn principle, gene therapy is an attractive option for invirions with envelopes from monkey or feline retroviherited blood-borne diseases, since gene transfer into ruses substantially increases the transduction rate of hematopoietic stem cells (HSC) with self-renewal capac-CD34 () hematopoietic precursor cells (Kelly et al., ity should lead to cure. In addition, though still poorly 2000). During the ex vivo infection phase, usage of cytocharacterized, HSC can easily be retrieved in relatively kines, ie, flt3-ligand, stem cell factor (SCF), and megalarge numbers in the bone marrow or by mobilization in karyocyte differentiating factors (MGDF), enable cell diblood and be thus physically accessible to gene transfer. vision without differentiation of early hematopoietic However, several clinical trials based on gene transfer progenitor cells. Coating of culture bags by a fibronectin into hematopoietic cells did not lead to efficient transfragment (CH296) also increases the transduction rate duction rates of these cells (reviewed in Candotti, 2000). by bringing together cells and viral particles (Hanenberg The clinical grade approved vectors enabling gene inteet al., 1996). Finally, modification of vectors by trimming gration into the genome of hematopoietic cells are all silencing sequences or introducing an insulator could derived from murine oncoretroviruses. Such vectors enhance transgene transcription rate. Taking into acwere found to be effective in the transduction of murine count these advances, it is not proper to compare results HSC but much less so for human HSC (Miller, 1992). of clinical trials performed very recently with those per-Two factors account for this discrepancy. Human HSC formed earlier. express low numbers of membrane receptors for am-