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基于合成信使核糖核酸的胶质母细胞瘤基因疗法：肿瘤坏死因子相关凋亡诱导配体信使核糖核酸协同增强基于磷酸酶和张力蛋白同源物信使核糖核酸的疗法。

Synthetic mRNA-based gene therapy for glioblastoma: TRAIL-mRNA synergistically enhances PTEN-mRNA-based therapy.

作者信息

Tang Xiangjun, Peng Hao, Xu Pengfei, Zhang Li, Fu Rui, Tu Hanjun, Guo Xingrong, Huang Kuanming, Lu Junti, Chen Hu, Dong Zhiqiang, Dai Longjun, Luo Jie, Chen Qianxue

机构信息

Department of Neurosurgery, Renmin Hospital of Wuhan University, 9 Zhangzhidong Road and 238 Jiefang Road, Wuhan, Hubei 430060, P.R. China.

Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.

出版信息

Mol Ther Oncolytics. 2022 Feb 2;24:707-718. doi: 10.1016/j.omto.2022.01.013. eCollection 2022 Mar 17.

DOI:10.1016/j.omto.2022.01.013
PMID:35317516
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8913249/
Abstract

Glioblastoma (GBM) is characterized as having high molecular heterogeneity and complexity, which can be well revealed by genomic study. A truly effective treatment for GBM should flexibly address its heterogeneities, complexity, and strong drug resistance. This study was performed to explore the effectiveness of an mRNA-based therapeutic strategy using synthesized PTEN-mRNA and TRAIL-mRNA in tumor cells derived from PTEN-deletion patients. The PTEN gene alterations were revealed by whole-exome sequencing of three paired clinical GBMs and selected as the therapy target. Patient-derived primary glioblastoma stem cells (GBM2) and a DBTRG-cell-derived xenograft were used to detect mRNA's cytotoxicity and tumor suppression . Following the successful synthesis of PTEN-mRNA and TRAIL-mRNA, the combinational treatment of PTEN-mRNA and TRAIL-mRNA significantly suppressed tumor growth compared with treatment with PBS (96.4%), PTEN-mRNA (89.7%), and TRAIL-mRNA (84.5%). The combinational application of PTEN-mRNA and TRAIL-mRNA showed synergistic inhibition of tumor growth, and the JNK pathway might be the major mechanism involved. This study provided a basis for an mRNA-based therapeutic strategy to be developed into an effective patient-tailored treatment for GBM.

摘要

胶质母细胞瘤（GBM）具有高度的分子异质性和复杂性，基因组研究能够很好地揭示这些特性。针对GBM的真正有效治疗方法应灵活应对其异质性、复杂性以及强大的耐药性。本研究旨在探索一种基于mRNA的治疗策略的有效性，该策略使用合成的PTEN - mRNA和TRAIL - mRNA作用于源自PTEN缺失患者的肿瘤细胞。通过对三对临床GBM进行全外显子测序揭示了PTEN基因改变，并将其选定为治疗靶点。使用患者来源的原发性胶质母细胞瘤干细胞（GBM2）和DBTRG细胞衍生的异种移植瘤来检测mRNA的细胞毒性和肿瘤抑制作用。成功合成PTEN - mRNA和TRAIL - mRNA后，与使用PBS（96.4%）、PTEN - mRNA（89.7%）和TRAIL - mRNA（84.5%）治疗相比，PTEN - mRNA和TRAIL - mRNA联合治疗显著抑制了肿瘤生长。PTEN - mRNA和TRAIL - mRNA的联合应用显示出对肿瘤生长的协同抑制作用，JNK通路可能是其中的主要机制。本研究为基于mRNA的治疗策略发展成为针对GBM的有效个体化治疗提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/10d4aefcde69/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/4080172556f6/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/88d7699b0c01/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/e260516a0d63/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/e75765d01ea8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/77e15213cb20/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/872a3984efc1/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/10d4aefcde69/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/4080172556f6/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/88d7699b0c01/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/e260516a0d63/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/e75765d01ea8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/77e15213cb20/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/872a3984efc1/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/65fa/8913249/10d4aefcde69/gr6.jpg

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