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|Type:||Artigo de periódico|
|Title:||Development Of A Liver-specific Tet-on Inducible System For Aav Vectors And Its Application In The Treatment Of Liver Cancer|
Di Scala M.
|Abstract:||Recombinant adeno-associated virus (rAAV) are effective gene delivery vehicles that can mediate long-lasting transgene expression. However, tight regulation and tissue-specific transgene expression is required for certain therapeutic applications. For regulatable expression from the liver we designed a hepatospecific bidirectional and autoregulatory tetracycline (Tet)-On system (Tet bidirAlb) flanked by AAV inverted terminal repeats (ITRs). We characterized the inducible hepatospecific system in comparison with an inducible ubiquitous expression system (Tet bidirCMV) using luciferase (luc). Although the ubiquitous system led to luc expression throughout the mouse, luc expression derived from the hepatospecific system was restricted to the liver. Interestingly, the induction rate of the Tet bidir Alb was significantly higher than that of Tet bidirCMV, whereas leakage of Tet bidir Alb was significantly lower. To evaluate the therapeutic potential of this vector, an AAV-Tet bidir-Alb-expressing interleukin-12 (IL-12) was tested in a murine model for hepatic colorectal metastasis. The vector induced dose-dependent levels of IL-12 and interferon-γ (IFN-γ), showing no significant toxicity. AAV-Tet bidir-Alb-IL-12 was highly efficient in preventing establishment of metastasis in the liver and induced an efficient T-cell memory response to tumor cells. Thus, we have demonstrated persistent, and inducible in vivo expression of a gene from a liver-specific Tet-On inducible construct delivered via an AAV vector and proved to be an efficient tool for treating liver cancer. © The American Society of Gene & Cell Therapy.|
|Appears in Collections:||Unicamp - Artigos e Outros Documentos|
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