文章：

在人类胶质母细胞瘤小鼠模型中基于aavp的靶向治疗：细胞毒性与自杀基因递送策略的比较

Targeted AAVP-based therapy in a mouse model of human glioblastoma: a comparison of cytotoxic versus suicide gene delivery strategies 

原文发布日期：2019-05-27 

英文摘要：

Glioblastoma persists as a uniformly deadly diagnosis for patients and effective therapeutic options are gravely needed. Recently, targeted gene therapy approaches are reemerging as attractive experimental clinical agents. Our ligand-directed hybrid virus of adeno-associated virus and phage (AAVP) is a targeted gene delivery vector that has been used in several formulations displaying targeting ligand peptides to deliver clinically applicable transgenes. Here we compared different constructs side-by-side in a tumor model, an orthotopic model of xenograft human glioblastoma cells stereotactically implanted in immunodeficient mice. We have used divergent therapeutic strategies for two AAVP constructs, both displaying a double-cyclic RGD4C motif ligand specific for alpha V integrins expressed in tumor vascular endothelium, but carrying different genes of interest for the treatment of intracranial xenografted tumors. One construct delivered tumor necrosis factor (TNF), a purely cytotoxic gene for antitumor activity (RGD4C-AAVP-TNF); in the other construct, we delivered Herpes simplex virus thymidine kinase (HSVtk) for in tandem molecular-genetic imaging and targeted therapy (RGD4C-AAVP-HSVtk) utilizing ganciclovir (GCV) for a suicide gene therapy. Both AAVP constructs demonstrated antitumor activity, with damage to the tumor-associated neovasculature and induction of cell death evident after treatment. In addition, the ability to monitor transgene expression with a radiolabeled HSVtk substrate pre and post GCV treatment demonstrated the theranostic potential of RGD4C-AAVP-HSVtk. We conclude that targeted AAVP constructs delivering either cytotoxic TNF or theranostic HSVtk followed by suicide gene therapy with GCV have comparable preclinical efficacy, at least in this standard experimental model. The results presented here provide a blueprint for future studies of targeted gene delivery against human glioblastomas and other brain tumors. 

摘要翻译： 

胶质母细胞瘤对患者而言始终是一种致命性疾病，目前亟需有效的治疗手段。近年来，靶向基因疗法作为具有吸引力的实验性临床制剂重新受到关注。我们开发的配体导向腺相关病毒-噬菌体杂交病毒（AAVP）是一种靶向基因递送载体，该载体已通过多种展示靶向配体肽的配方应用于临床适用转基因的递送。本研究在肿瘤模型——即免疫缺陷小鼠颅内立体定向移植的人胶质母细胞瘤原位异种移植模型中，对不同构建体进行了平行比较。我们针对两种AAVP构建体采用了差异化的治疗策略：二者均展示对肿瘤血管内皮表达的αV整合素具有特异性的双环RGD4C motif配体，但携带用于治疗颅内异种移植瘤的不同目的基因。一种构建体递送纯粹用于抗肿瘤活性的细胞毒性基因——肿瘤坏死因子（TNF）（RGD4C-AAVP-TNF）；另一种构建体则递送单纯疱疹病毒胸苷激酶（HSVtk），通过联合使用更昔洛韦（GCV）实现自杀基因治疗，同时具备分子遗传成像功能（RGD4C-AAVP-HSVtk）。两种AAVP构建体均显示出抗肿瘤活性，治疗后可见肿瘤相关新生血管系统损伤及细胞死亡诱导。此外，通过使用放射性标记的HSVtk底物在GCV治疗前后监测转基因表达，证明了RGD4C-AAVP-HSVtk的诊疗一体化潜力。我们的结论是：在至少这种标准实验模型中，递送细胞毒性TNF的靶向AAVP构建体与采用GCV进行自杀基因治疗的诊疗一体化HSVtk构建体具有相当的临床前疗效。本研究结果为后续针对人胶质母细胞瘤及其他脑部肿瘤的靶向基因递送研究提供了蓝图。

原文链接：

Targeted AAVP-based therapy in a mouse model of human glioblastoma: a comparison of cytotoxic versus suicide gene delivery strategies