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Transforming growth factor (TGF)-β is a potent cytokine with multiple biological activities, which has become an attractive target in glioblastoma because of its immunosuppressive properties and its role in angiogenesis, migration and invasion. Although the pathogenic function of TGF-β1 and TGF-β2 in glioblastoma is well defined, therapeutic targeting remains a challenge. Here we characterize the effects of two novel TGF-β1- or TGF-β2-specific phosphorothioate locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, ISTH1047 and ISTH0047 respectively, on the downstream signaling and growth of human LN-308 and murine SMA-560 glioma cells in vitro. Furthermore, we determined the effect of both antisense molecules on target inhibition and survival in orthotropic xenogeneic (LN-308) and syngeneic (SMA-560) in vivo glioma models. Both antisense oligonucleotides silence their corresponding target and inhibit downstream SMAD-2 phosphorylation in a concentration- and time-dependent manner. Moreover, inhibition of TGF-β1 or TGF-β2 mRNA expression by ISTH1047 or ISTH0047 reduces both the migrating and invasive potential of LN-308 and SMA-560 cells, with no effect on cell viability. Natural killer (NK) cells co-cultured with TGF-β2-depleted LN-308 glioma cells, exhibit increased lytic activity against the tumor cells. In vivo systemic administration of ISTH1047 or ISTH0047 significantly suppresses TGF-β1 or TGF-β2 mRNA expression, as well as the mRNA expression of the down-stream target PAI-1 in murine glioma-bearing hemispheres. Currently, we are investigating the therapeutic effect of ISTH1047 or ISTH0047 in the orthotopic glioma models. These data suggest that targeting TGF-β1 or TGF-β2 using these novel antisense oligonucleotides represents a promising approach to inhibit aberrant TGF-β signaling in glioblastoma with potential therapeutic benefit.