Gene delivery to tumor microenvironment enhances survival of glioblastoma mice

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Harvard scientists demonstrate the potential of using exosome-associated AAV (exo-AAV) vector as a powerful tool for gene delivery to brain. Delivery of anti-tumor cytokine, interferon beta, using exo-AAV into the tumor stroma enhanced survival in a mouse model of glioblastoma.

Recombinant AAV vectors have rapidly advanced to the forefront of gene therapy in the past decade. Exosome-associated AAV vector (Exo-AAV) as a novel gene delivery system was first reported by Prof. Casey Maguire in 2012. He reported that a portion of AAV isolated from media is associated with exosomes and named it as exo-AAV. A later research by his team showed that exo-AAV could be easily produced in five days after a simple high-speed centrifugation step and outperforms conventional AAV in transducing brain cells and crossing the blood-brain barrier.

In the present study, Prof. Maguire’s team at the Harvard Medical School have demonstrated the potential of exo-AAV vector in targeting glioblastoma (GBM). AAV has been tested before to deliver transgenes to treat GBM, however, its direct injection to the tumor resulted in limited duration of transgene expression and intravenous injections led to ineffective therapy and high toxicity.

To overcome this, delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells was tested in the study. The hypothesis was that tumor stromal cells, including reactive astrocytes and tumor-associated macrophage/microglia (TAMs) which are linked tumorigenesis could provide a more stable and localized reservoir of therapy as they are more differentiated than fast dividing tumor cells.

The test this, the team delivered exo-AAVs encoding the anti-tumor cytokine, interferon beta, into the tumor stroma of a mouse model of GBM. To obtain targeted transduction of TAMs and reactive astrocytes, specific promoters targeting these cell types were used. Results published in the Journal of Neuro-Oncology showed significant enhancement in survival in the exo-AAV treated mice compared to controls.

The study indicates that manipulating tumor microenvironment using exo-AAV could be used as powerful tool for gene therapy for glioblastoma and other cancers.

Source: Volak A et al., Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery. Journal of Neuro-Oncology, May 2018. DOI