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Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives. 基因疗法治疗胃肠道疾病的潜力:进展与未来展望。
IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-18 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.007
Ning-Ning Yue, Hao-Ming Xu, Jing Xu, Min-Zheng Zhu, Yuan Zhang, Cheng-Mei Tian, Yu-Qiang Nie, Jun Yao, Yu-Jie Liang, De-Feng Li, Li-Sheng Wang

Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.

随着对胃肠道疾病(包括炎症性肠病、胃肠道癌症和胃食管反流病)发病机制认识的不断深入,人们发现了许多新的治疗靶点。这些发现为开发治疗胃肠道疾病的基因治疗策略提供了令人兴奋的可能性。这些策略包括基因替换、基因增强、基因过表达、基因功能阻断和转基因体细胞移植。在这篇综述中,我们将介绍胃肠病学领域的重要基因治疗靶点和靶向传递系统。此外,我们还全面概述了与胃肠道疾病相关的基因治疗的最新进展,并阐明了创新基因编辑技术在治疗这些疾病中的应用。这些发展正在推动胃肠道疾病治疗领域的一场革命。最后,我们讨论了当前面临的挑战(尤其是安全性、口服疗效和成本),并探讨了在胃肠道疾病临床治疗中实施基因疗法的潜在未来方向。
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引用次数: 0
Endogenous H3.3K27M derived peptide restricted to HLA-A∗02:01 is insufficient for immune-targeting in diffuse midline glioma. 局限于HLA-A*02:01的内源性H3.3K27M衍生肽不足以用于弥漫性中线神经胶质瘤的免疫靶向。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-15 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.005
Stacie S Wang, Kirti Pandey, Katherine A Watson, Rebecca C Abbott, Nicole A Mifsud, Fiona M Gracey, Sri H Ramarathinam, Ryan S Cross, Anthony W Purcell, Misty R Jenkins

Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape. We developed a second-generation CAR targeting an HLA-A∗02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, binding to cells pulsed with the H3.3K27M peptide. However, we were unable to observe scFv binding, CAR T cell activation, or cytotoxic function against H3.3K27M+ patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3.3K27M26-35-HLA-A∗02:01 peptide on these patient-derived models. Interestingly, other non-mutated peptides from DMG were detected bound to HLA-A∗02:01 and other class I molecules, including a novel HLA-A3-restricted peptide encompassing the K27M mutation and overlapping with the H3 K27M26-35-HLA-A∗02:01 peptide. These results suggest that targeting the H3 K27M26-35 mutation in context of HLA-A∗02:01 may not be a feasible immunotherapy strategy because of its lack of presentation. These findings should inform future investigations and clinical trials in DMG.

弥漫性中线胶质瘤(DMG)是一种预后极差的儿童脑肿瘤。嵌合抗原受体(CAR)T细胞疗法最近在DMG中取得了一些成功,但可能需要靶向多个肿瘤特异性靶点以避免抗原逃逸。我们开发了一种针对DMG中HLA-a*02:01限制性组蛋白3K27M表位的第二代CAR,DMG是先前肽疫苗接种和T细胞受体模拟物的靶点。这些CAR T细胞表现出与用H3.3K27M肽脉冲的细胞的特异性、可滴定的结合。然而,我们无法观察到针对H3.3K27M+患者衍生模型的scFv结合、CAR T细胞活化或细胞毒性功能。尽管使用了敏感的免疫肽组学,但我们无法在这些患者衍生的模型上检测到H3.3K27M26-35-HLA-A*02:01肽。有趣的是,检测到来自DMG的其他非突变肽与HLA-A*02:01和其他I类分子结合,包括一种新的HLA-A3限制肽,该肽包含K27M突变并与H3 K27M26-35-HLA-A*02:01肽重叠。这些结果表明,在HLA-A*02:01的背景下靶向H3 K27M26-35突变可能不是一种可行的免疫治疗策略,因为它缺乏表现。这些发现应该为DMG的未来研究和临床试验提供信息。
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引用次数: 0
Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution. 以单细胞分辨率揭示小鼠髓母细胞瘤中由溶瘤病毒驱动的免疫重塑。
IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-07-19 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.07.006
Jack Hedberg, Adam Studebaker, Luke Smith, Chun-Yu Chen, Jesse J Westfall, Maren Cam, Amy Gross, Ilse Hernandez-Aguirre, Alexia Martin, Doyeon Kim, Ravi Dhital, Yeaseul Kim, Ryan D Roberts, Timothy P Cripe, Elaine R Mardis, Kevin A Cassady, Jeffrey Leonard, Katherine E Miller

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma.

为限制肿瘤感染而改良的肿瘤溶解病毒是一种很有前景的癌症免疫疗法,但人们对驱动其在肿瘤微环境中的活性和结果的因素还有很多不了解。在这里,我们报告了溶瘤性单纯疱疹病毒 C134,它以前在胶质母细胞瘤小鼠模型中发挥了依赖 T 细胞的疗效,但在髓母细胞瘤小鼠模型中却发挥了不依赖 T 细胞的疗效,这表明这种溶瘤病毒在不同的肿瘤中使用了不同的机制。我们研究了 C134 在小鼠髓母细胞瘤中的表现,利用单细胞 RNA 测序,以全转录组分辨率绘制了 C134 诱导的跨细胞类型、时间点和髓母细胞瘤亚组模型的基因表达变化图。我们的研究详述了大量溶瘤病毒诱导的髓母细胞瘤浸润免疫细胞转录重塑,10个单核细胞和巨噬细胞亚群对C134共同表现出M1样反应,并建议将C134作为一种潜在的髓母细胞瘤新疗法进行研究。
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引用次数: 0
Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme. 一种以 EpCAM 为靶点的 Ras 降解酶能有效并有选择性地消灭肿瘤细胞。
IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-27 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.06.002
Valentina Palacio-Castañeda, Bas van de Crommert, Elke Verploegen, Mike Overeem, Jenny van Oostrum, Wouter P R Verdurmen

Despite decades of efforts, an urgent need remains to develop tumor cell-selective rat sarcoma (Ras)-targeting therapies that can treat patients with Ras-driven tumors. Here we report modular engineered proteins that degrade Ras selectively in tumor cells that overexpress the tumor cell marker epithelial cell adhesion molecule (EpCAM) by fusing the Ras degrader Ras-Rap1-specific endopeptidase with the translocation domain of the Pseudomonas aeruginosa exotoxin A (ETA) or diphtheria toxin (DT). Redirection to EpCAM is achieved by a designed ankyrin repeat protein. In two-dimensional tumor cell cultures, complete degradation of Ras proteins after 24 h was observed with EpCAM-targeted Ras degraders fused to ETA or DT in EpCAM-overexpressing MCF7 and HCT116 cells, with median inhibition concentration values at sub-nanomolar levels. The viability of EpCAM-low non-cancerous fibroblasts remained unaffected. In a three-dimensional (3D) tumor-on-a-chip system that mimics the natural tumor microenvironment, effective Ras degradation and selective toxicity toward tumor cells, particularly with the ETA-fused constructs, was determined on-chip. To conclude, we demonstrate the potential of modular engineered proteins to kill tumor cells highly selectively by simultaneously exploiting EpCAM as a tumor-specific cell surface molecule as well as Ras as an intracellular oncotarget in a 3D system mimicking the natural tumor microenvironment.

尽管经过数十年的努力,但目前仍迫切需要开发具有肿瘤细胞选择性的大鼠肉瘤(Ras)靶向疗法,以治疗 Ras 驱动的肿瘤患者。在这里,我们报告了通过将 Ras 降解剂 Ras-Rap1 特异性内肽酶与铜绿假单胞菌外毒素 A(ETA)或白喉毒素(DT)的易位结构域融合,在过度表达肿瘤细胞标记物上皮细胞粘附分子(EpCAM)的肿瘤细胞中选择性降解 Ras 的模块化工程蛋白。与 EpCAM 的重定向是通过设计的杏仁蛋白重复蛋白实现的。在二维肿瘤细胞培养中,使用融合了 ETA 或 DT 的 EpCAM 靶向 Ras 降解剂,在 EpCAM 过表达的 MCF7 和 HCT116 细胞中,24 小时后可观察到 Ras 蛋白的完全降解,中位抑制浓度值在亚纳摩尔水平。EpCAM含量较低的非癌成纤维细胞的活力不受影响。在模拟天然肿瘤微环境的三维(3D)肿瘤芯片系统中,芯片上确定了有效的 Ras 降解和对肿瘤细胞的选择性毒性,特别是与 ETA 融合的构建体。总之,我们证明了模块化工程蛋白在三维系统中模拟天然肿瘤微环境,同时利用作为肿瘤特异性细胞表面分子的 EpCAM 和作为细胞内肿瘤靶点的 Ras,高度选择性地杀死肿瘤细胞的潜力。
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引用次数: 0
Radiovirotherapy at twenty. 放射病毒治疗,20岁。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.003
David Dingli
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引用次数: 0
PTEN potentiation of oncolytic HSV therapy for glioblastoma. PTEN增强溶瘤性HSV治疗胶质母细胞瘤的作用。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.005
Christian Migliarese, Hiroaki Wakimoto
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引用次数: 0
Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response. 靶向白细胞介素-15途径的重组痘苗病毒的溶瘤治疗引发协同反应。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.002
Yasmin Shakiba, Pavel O Vorobyev, Gaukhar M Yusubalieva, Dmitry V Kochetkov, Ksenia V Zajtseva, Marat P Valikhov, Vladimir A Kalsin, Fedor G Zabozlaev, Alevtina S Semkina, Alexander V Troitskiy, Vladimir P Baklaushev, Peter M Chumakov, Anastasia V Lipatova

We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer.

我们开发了溶瘤痘苗病毒LIVP株的重组变体,表达白细胞介素-15 (IL-15)或其受体亚单位α (IL-15Rα)来刺激IL-15依赖的免疫细胞。我们在体外和体内使用小鼠CT26结肠癌和4T1乳腺癌模型评估了它们单独或相互联合的溶瘤活性。我们证明了这些重组变体的混合物可以促进IL-15/IL-15Rα复合物的产生。体外研究表明,4T1乳腺癌细胞对所开发的重组病毒更敏感。体内研究显示,在接受LIVP-IL15-RFP和LIVP-IL15Ra-RFP联合治疗的4T1乳腺癌同基因小鼠中,生存率显著提高,肿瘤消退。组织学分析显示肿瘤区淋巴细胞募集,对动物肝脏和脾脏未见有害影响。在接受联合治疗的小鼠中,评估肿瘤浸润淋巴细胞表明细胞毒性T细胞和巨噬细胞的深度激活。因此,我们的实验表明,同时注射LIVP-IL15-RFP和LIVP-IL15Ra-RFP对乳腺癌小鼠具有较好的溶瘤效果。这些重组变体的联合治疗代表了开发新的乳腺癌免疫疗法的有效和通用的方法。
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引用次数: 1
Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers. 通过转染嵌合抗原受体或双特异性T细胞接合体的mRNA增强γδ T细胞的有效性。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.007
Scott A Becker, Brian G Petrich, Bing Yu, Kristopher A Knight, Harrison C Brown, Sunil S Raikar, Christopher B Doering, H Trent Spencer

Adoptive cell therapy (ACT) utilizing γδ T cells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific T cell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ T cells with CAR or secreted bispecific T cell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ T cells. Using a CD19-specific CAR, approximately 60% of γδ T cells are modified after mRNA electroporation and these cells show potent anticancer activity in vitro and in vivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both in vitro and in vivo, and promotes killing of target cells by modified and unmodified γδ T cells. Taken together, we show that transient transfection of γδ T cells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.

利用γδ T细胞的过继细胞疗法(ACT)正成为治疗癌症的一种有前景的选择,因为它提供了一种现成的同种异体产品,安全、有效且临床有效。设计或增强ACT免疫能力细胞的方法,如嵌合抗原受体(CARs)的表达或与双特异性T细胞结合者的联合治疗,已经提高了ACT的特异性和细胞毒性潜力,并在临床前和临床环境中显示出巨大的希望。在这里,我们测试了用CAR或分泌的双特异性T细胞接合器(sBite) mRNA电穿孔γδ T细胞是否是一种有效的方法来改善γδ T细胞的细胞毒性。使用cd19特异性CAR,大约60%的γδ T细胞在mRNA电穿孔后被修饰,这些细胞在体外和体内对两种cd19阳性癌细胞系显示出强大的抗癌活性。此外,CD19 sBite的表达和分泌增强了γδ T细胞的体外和体内毒性,并促进修饰和未修饰的γδ T细胞杀伤靶细胞。综上所述,我们表明通过电穿孔瞬时转染CAR或sBite mRNA的γδ T细胞可以作为癌症治疗的有效治疗平台。
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引用次数: 1
Expanding the landscape of TCR gene therapy targeting MAGE. 拓展靶向MAGE的TCR基因治疗领域。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.004
Zhiyuan Mao, John K Lee
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引用次数: 0
Attack of the clones: An NK cell origins story. 克隆的攻击:NK细胞起源的故事。
IF 5.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.02.010
Joseph R Caporale, Dean A Lee
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引用次数: 0
期刊
Molecular Therapy Oncolytics
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