A Walk on the Fine Line Between Reward and Risk: AAV-IFNβ Gene Therapy for Glioblastoma: A Dissertation

摘要: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The current standard-of-care treatment including surgery, radiation temozolomide (TMZ) chemotherapy does not prolong survival satisfactorily. Here we have tested feasibility, efficacy safety of a potential gene therapy approach using AAV as delivery vehicle for GBM. Interferon-beta (IFNβ) cytokine molecule also having pleiotropic anticancerous properties. Previously it has been shown by our group that mediated local (intracranial) human IFNβ (hIFNβ) could be an effective non-invasive glioblastoma (U87) in orthotopic xenograft mouse model.But one major challenges to treat GBM effectively clinics its highly invasive property, study first sought test therapeutic model (GBM8) model. One limitation these mice are immune-compromised. Moreover, interact with cross-species receptors, influence immune systems on remains largely untested. Therefore immune-competent model, next treated syngeneic (GL261) (C57B6) encoding species-matched (mIFNβ). We if combination this standard chemotherapeutic drug more than any modes alone. Finally, long term AAV-mIFNβ healthy C57B6 mice. Next, hypothesized global genetic engineering cells expressing secretory protein like hIFNβ beneficial invasive, migratory distal multifocal hypothesis systemic AAV9 vectors GBM8 tumor nude Using vivo bioluminescence imaging associated firefly luciferase activity, assay histological analysis brains AAV-hIFNβ therapeutically at early growth phase However, route far superior treating tumors. Nonetheless, both routes, significantly reduced when later In GL261 study, show alone or TMZ can provide significant benefit over control only treatment, respectively. animals eventually succumb Safety shows body weight loss some groups, whereas without noticeable changes external…