文章：

诱导Caspase9介导的自杀基因在MSC癌症基因治疗中的应用

Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy 

原文发布日期：2018-06-29 

英文摘要：

Cellular therapies based on mesenchymal stromal/stem cells (MSC) are promising strategies in regenerative medicine and oncology. Despite encouraging results, there is still some level of concerns on inoculating MSC in cancer patients. To face this issue, one possibility resides in engineering MSC by incorporating a suicide gene in order to control their fate once infused. Strategies based on Herpes Simplex Virus Thymidine Kinase (HSV-TK) and the Cytosine Deaminase genes have been developed and more recently a novel suicide gene, namely, iCasp9, has been proposed. This approach is based on a variant of human Caspase9 that binds with high affinity to a synthetic, bioinert small molecule (AP20187) leading to cell death. Based on this technology so far marginally applied to MSC, we tested the suitability of iCasp9 suicide strategy in MSC to further increase their safety. MSC have been transfected by a lentiviral vector carrying iCasp9 gene and then tested for viability after AP20187 treatment in comparison with mock-transfected cells. Moreover, accounting our anti-tumor approaches based on MSC expressing potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), we generated adipose MSC co-expressing iCasp9 and TRAIL successfully targeting an aggressive sarcoma type. These data show that anti-cancer and suicide mechanisms can coexist without affecting cells performance and hampering the tumoricidal activity mediated by TRAIL. In conclusion, this study originally indicates the suitability of combining a MSC-based anti-cancer gene approach with iCasp9 demonstrating efficiency and specificity. 

摘要翻译： 

基于间充质基质/干细胞（MSC）的细胞疗法是再生医学和肿瘤学领域的前沿策略。尽管已取得鼓舞人心的成果，但在癌症患者体内接种MSC仍存在一定担忧。为解决这一问题，可通过在MSC中整合自杀基因以控制其输注后的命运。目前除已开发的基于单纯疱疹病毒胸苷激酶（HSV-TK）和胞嘧啶脱氨酶基因的策略外，近期又提出了一种新型自杀基因——iCasp9。该技术采用与人源Caspase9高亲和力结合的人工合成生物惰性小分子（AP20187），可诱导细胞死亡。基于这项此前在MSC中应用有限的技术，我们验证了iCasp9自杀基因系统在MSC中的适用性，以进一步提升其安全性。通过慢病毒载体将iCasp9基因转染至MSC后，经AP20187处理的实验组细胞存活率显著低于空白转染组。此外，结合我们基于表达高效抗癌配体TRAIL（肿瘤坏死因子相关凋亡诱导配体）的MSC抗肿瘤方案，我们成功构建了共表达iCasp9与TRAIL的脂肪源MSC，可有效靶向侵袭性肉瘤。数据显示抗癌机制与自杀机制可协同共存，既不影响细胞功能，也不削弱TRAIL介导的肿瘤杀伤活性。本研究首次证实了iCasp9与MSC抗癌基因疗法联用的可行性，兼具高效性与特异性。

原文链接：

Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy