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Background <p>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.</p> Methods <p>We selected <i>micoRNAs</i> (<i>miRs</i>) 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 <i>miR</i>-dependent manner (<i>miR</i>-dependent GE). Additionally, we developed mosaic-capsids that consist of braintropic and universal capsids, which deliver genes into GIC brain tumors.</p> Results <p>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 <i>miR</i>-dependent GE prevented GIC tumorigenesis in the brain and extended the survival time of tumor-bearing mice.</p> Conclusion <p>These data indicate that the mosaic-capsids AAV containing a <i>miR</i>-dependent GE represents a novel therapeutic virus for GBM with fewer side effects.</p>

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Novel strategy to target glioblastoma-initiating cells using a braintropic adeno-associated virus carrying a miR-dependent genome-editing system

  • 期刊论文

  • 发表日期：

    2025年4月12日

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  • Zhe Wang,
  • Peilin Zou,
  • Zhenzhong Chen,
  • Jiahui Hou,
  • You Lee Son,
  • Daisuke Yamashita,
  • Toru Kondo

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

These data indicate that the mosaic-capsids AAV containing a miR-dependent GE represents a novel therapeutic virus for GBM with fewer side effects.