AAV transduction of human glioblastoma cell lines induces perturbation in cell proliferation

Glioblastoma (GBM) is a highly aggressive type of brain cancer associated with poor prognosis due to limited effective treatment options. Adeno-associated viral (AAV) vector-based gene therapy strategies have demonstrated promise in preclinical models of GBM, but inter- and intratumor cellular heterogeneity poses a challenge for tumor-specific targeting. Here, we screened a panel of 15 AAV serotypes against the widely used human GBM cell line U-87 MG, and five primary patient-derived GBM cell lines to characterize their transduction efficiencies. AAV1, AAV2, AAV1/2, AAV6, and AAV6.2 were the most efficient and consistent serotypes across cell lines, capable of differentially transducing CD44-expressing cells in culture, albeit non-selectively. Interestingly, we observed a reduction in cell number and proliferation in certain cell lines, which correlated with AAV transduction efficiency. This phenomenon was shown to be a cytostatic rather than cytotoxic effect on GBM cells, occurring independently of promoter sequence and transgene expression. The anti-proliferative effect was particularly pronounced in two patient-derived cell lines, where cell proliferation decreased by nearly 80%. Altogether, our results provide a foundation for future studies optimizing AAV-mediated transduction in the diverse GBM cell population and demonstrate the potential to harness the natural properties of AAV in treatment development for brain cancers.