Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia.
Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia.
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DOI：
10.1038/mtm.2016.53
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发表时间：
2016
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--
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许多临床试验正在利用间充质干细胞（MSC）治疗严重的肢体缺血，主要是因为它们能够分泌促进血管再生的信号。这些细胞已经证明了临床安全性，但它们的功效有限，可能是因为这些旁分泌信号以亚治疗水平分泌。在这些研究中，通过用慢病毒工程化MSC以过表达血管内皮生长因子（VEGF）来评估细胞和基因治疗的组合。为了达到临床依从性，病毒插入的数量限制在1-2个拷贝/细胞，并使用具有临床安全性的组成型启动子。与假手术对照组相比，MSC/VEGF在血流恢复方面显示出统计学显著性增加，并且与未转导的MSC相比，改善更为一致。MSC/VEGF的安全性在基因组稳定性、排除致瘤性和体内无水肿或血管瘤方面进行了评估。在保留方面，注射的MSC/VEGF显示出随时间的稳定下降，只有非常小部分的MSC/VEGF保留长达4.5个月。已完成的其他安全性研究包括不存在可复制慢病毒、无菌检查和不存在VSV-G病毒包膜编码质粒。这些临床前研究是针对一个计划的1期临床试验，以治疗严重的肢体缺血。
Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.
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