Wang Zhe, Zou Peilin, Chen Zhenzhong, Hou Jiahui, Son You Lee, Yamashita Daisuke, Kondo Toru
Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0815, Japan.
Department of Neurosurgery, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.
Br J Cancer. 2025 Apr 12. doi: 10.1038/s41416-025-03007-3.
Since glioblastoma (GBM)-initiating cells (GICs) were identified as the cells-of-origin for GBM, various GIC factors have been analyzed as potential therapeutic targets. However, these targets are also present in normal cells outside of the brain, raising concerns about potential side effects when directly targeted. The aim of this study is to develop a novel method that specifically eradicates GICs with reducing side effects.
We selected micoRNAs (miRs) that are significantly decreased in GICs compared to normal cells and developed a genome-editing (GE) system that knocks out a functional GIC factor in a miR-dependent manner (miR-dependent GE). Additionally, we developed mosaic-capsids that consist of braintropic and universal capsids, which deliver genes into GIC brain tumors.
Systemic administration of the mosaic-capsids Adeno-associated virus (AAV) carrying a miR-dependent GFP expression cassette selectively expressed GFP in GICs transplanted into the brains of immunodeficient mice, without expression in either mouse brain cells or non-brain tissues. The mosaic-capsids AAV carrying a miR-dependent GE prevented GIC tumorigenesis in the brain and extended the survival time of tumor-bearing mice.
These data indicate that the mosaic-capsids AAV containing a miR-dependent GE represents a novel therapeutic virus for GBM with fewer side effects.
自从胶质母细胞瘤（GBM）起始细胞（GICs）被确定为GBM的起源细胞以来，各种GIC因子已被作为潜在治疗靶点进行分析。然而，这些靶点在脑外的正常细胞中也存在，这引发了对直接靶向时潜在副作用的担忧。本研究的目的是开发一种新方法，能特异性根除GICs并减少副作用。
我们选择了与正常细胞相比在GICs中显著减少的微小RNA（miRs），并开发了一种基因组编辑（GE）系统，该系统以miR依赖的方式敲除功能性GIC因子（miR依赖的GE）。此外，我们开发了由嗜脑衣壳和通用衣壳组成的嵌合衣壳，其可将基因传递至GIC脑肿瘤中。
全身给予携带miR依赖的绿色荧光蛋白（GFP）表达盒的嵌合衣壳腺相关病毒（AAV），在移植到免疫缺陷小鼠脑内的GICs中选择性表达GFP，而在小鼠脑细胞或非脑组织中均无表达。携带miR依赖的GE的嵌合衣壳AAV可预防脑内GIC肿瘤发生，并延长荷瘤小鼠的生存时间。
这些数据表明，含有miR依赖的GE的嵌合衣壳AAV代表一种新型的副作用较少的GBM治疗性病毒。
