(306d) Adeno-Associated Virus-Based Gene Therapy to Treat Glioblastomas

Glioblastomas (GBMs) comprise the most aggressive, highly heterogeneous and malignant brain tumors. The FDA has approved chemotherapies (temozolomide, epirubicin) and biotherapy (bevacizumab), but most GBM patients develop drug resistance and become recurrent with <10% of five-year survival rate. We recently developed a mitochondrial luminoptogenetic (cmLumiOpto) technology by synthesizing cancer mitochondria-depolarizing genes. This study aimed to evaluate the feasibility of cmLumiOpto-mediated gene therapy to treat aggressive GBM. First, we constructed a recombinant adeno-associated virus (rAAV) to deliver and express the cmLumiOpto genes, and successfully developed a robust, scalable, high-yield, suspensive AAV biomanufacturing platform using stirred-tank bioreactor and liquid chromatography. In vitro evaluations of AAV demonstrated high transduction efficiency, functional gene expression, and high cytotoxicity to multiple GBM cell lines. The GBM line (G251-FLuc) intracranially xenografted mouse models showed that the AAV-carrying cmLumiOpto gene had high and functional expression in GBM tumor and effectively inhibited tumor growth as monitored with IVIS imaging and validated with MRI imaging. The patient-derived xenograft mouse models validated the high efficacy of GBM treatment by AAV-mediated gene therapy. We will further develop and fully evaluate the anti-GBM capability of this novel gene therapy, which has great potential to improve the life quality of patients.