Systemic AAV9-IFN? gene delivery treats highly invasive glioblastoma.

ABSTRACT: Complete surgical removal of all glioblastoma (GBM) cells is impossible due to extensive infiltration into brain parenchyma that ultimately leads to tumor recurrence. The current standard of care affords modest improvements in survival. New therapeutic interventions are needed to prevent recurrence. Local AAV-hIFN? gene delivery to the brain was previously shown to eradicate noninvasive orthotopic U87 tumors in mice. However, widespread CNS gene delivery may be necessary to treat invasive GBMs. Here we investigated the therapeutic effectiveness of systemically infused AAV9-hIFN? against an invasive orthotopic GBM8 model.Mice bearing human GBM8 brain tumors expressing firefly luciferase (Fluc) were treated systemically with different doses of scAAV9-hIFN? vector. Therapeutic efficacy was assessed by sequential bioluminescence imaging of tumor Fluc activity and animal survival. Brains were analyzed post mortem for the presence and appearance of tumors. Two transcriptionally restricted AAV vectors were used to assess the therapeutic contribution of peripheral hIFN?.Systemic infusion of scAAV9-hIFN? vector induced complete regression of established GBM8 tumors in a dose-dependent manner. The efficacy of this approach was also dependent on the stage of tumor growth at the time of treatment. We also showed that peripherally produced hIFN? contributed considerably to the therapeutic effect of scAAV9-hIFN?. A comparative study of systemic and unilateral intracranial delivery of scAAV9-hIFN? in a bilateral GBM8 tumor model showed the systemic route to be the most effective approach for treating widely dispersed tumors.Systemic delivery of AAV9-IFN? is an attractive approach for invasive and multifocal GBM treatment.

SUBMITTER: GuhaSarkar D 

PROVIDER: S-EPMC5063516 | biostudies-other | 2016 Nov

REPOSITORIES: biostudies-other