以抑癌基因PTEN为标靶的基因疗法对皮肤T细胞淋巴瘤的治疗作用和机制

The pathogenesis of Cutaneous T-cell lymphoma (CTCL) remains unclear and there is no standard treatment therapy available, therefore, the improvement of prognosis is still required. Previous studies found that the mRNA and protein levels of anti-tumor gene PTEN were lower in CTCL cells than in normal T cells. In several kinds tumors, over expression of PTEN induced blockage of PI3/AKT kinase signalling pathway, eventually induce cell apoptosis. However, the function of PTEN in CTCL is still unclear. Although type 5 adenovirus (ad5) based gene therapy has been used in clinical, the infectivity of ad5 to T cells were low, which limilted the usage of ad5 for transfering PTEN into CTCL cells. Our previous research indicated that the infectivity of novel adenovirus vector ad5/35, which replaced the ad5 fiber with ad35 fiber, was much improved infectivity in T cells. Therefore, in this project, we plan to transfer normal PTEN gene in to CTCL cells with ad5/35 vector by producing novel adenovirus ad5/35-PTEN, and investigate the anti-tumor effects and mechanisms in CTCL treatment. In this project, we are going to test PTEN expression in CTCL tissue; confirm the infectivity of ad5/35 is greater than ad5 in T cells; observe ad5/35-PTEN infection induced PTEN protein over expression and cell apoptosis; investigate the possible mechanisms involved in PTEN over expression in CTCL; prove the safety of ad5/35 in animal model. Through this project, we expect to elucidate the functions of ad5/35-PTEN in CTCL treatment and explore the possible mechanisms in volved in PTEN over expression in CTCL. Through this project, we will creat a novel treatment therapy for CTCL.

皮肤T细胞淋巴瘤（CTCL）的发病机制不清，没有统一、有效的治疗方案。研究发现CTCL中抑癌基因PTEN的蛋白水平均低于正常组织。在多种肿瘤中，过表达PTEN蛋白可以通过抑制PI3/AKT激酶诱导细胞凋亡，但在CTCL中具体机制不清。5型腺病毒（ad5）介导的基因疗法已应用于临床，但ad5对T细胞的感染效率低下。本项目计划用前期制造的ad5/35腺病毒载体将正常PTEN基因导入CTCL细胞，研究其在CTCL中的作用和具体机制。包括检测PTEN在CTCL中的表达水平；验证ad5/35对T细胞的感染效率优于ad5；观察ad5/35-PTEN在CTCL中诱导的PTEN过表达和细胞凋亡；分析PTEN过表达后的具体抗肿瘤机制；证明ad5/35体内使用的安全性。本项目的目标是阐明以PTEN为标靶，以ad5/35为载体的靶向治疗在CTCL中的作用和机制。本项目将为CTCL的靶向治疗开创新方法探索新机制。