Bortolanza, S. (Sergia)
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- Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication(Nature Publishing Group, 2006) Civeira, M.P. (María Pilar); Riezu-Boj, J.I. (José Ignacio); Alfaro, C. (Carlos); Perez-Gracia, J.L. (Jose Luis); Larrea, E. (Esther); Murillo, O. (Oihana); Azpilicueta, A. (Arantza); Hervas-Stubbs, S. (Sandra); Melero, I. (Ignacio); Prieto, J. (Jesús); Huarte, E. (Eduardo); Bortolanza, S. (Sergia); Tirapu, I. (Íñigo); Hernandez-Alcoceba, R. (Rubén); Arina, A. (Ainhoa)Recombinant adenovirus administration gives rise to transgene-independent effects caused by the ability of the vector to activate innate immunity mechanisms. We show that recombinant adenoviruses encoding reporter genes trigger IFN-alpha and IFN-beta transcription from both plasmacytoid and myeloid mouse dendritic cells. Interestingly, IFN-beta and IFN-alpha5 are the predominant transcribed type I IFN genes both in vitro and in vivo. In human peripheral blood leukocytes type I IFNs are induced by adenoviral vectors, with a preponderance of IFN-beta together with IFN-alpha1 and IFN-alpha5 subtypes. Accordingly, functional type I IFN is readily detected in serum samples from human cancer patients who have been treated intratumorally with a recombinant adenovirus encoding thymidine kinase. Despite inducing functional IFN-alpha release in both mice and humans, gene transfer by recombinant adenoviruses is not interfered with by type I IFNs either in vitro or in vivo. Moreover, IFN-alpha does not impair replication of wild-type adenovirus. As a consequence, cancer gene therapy strategies with defective or replicative-competent adenoviruses are not expected to be hampered by the effect of the type I IFNs induced by the vector itself. However, type I IFN might modulate antitumor and antiadenoviral immune responses and thus influence the outcome of gene immunotherapy.
- Treatment of pancreatic cancer with an oncolytic adenovirus expressing Interleukin-12 in syrian hamsters(Nature Publishing Group, 2009) González-Aseguinolaza, G. (Gloria); Ortiz-de-Solorzano, C. (Carlos); Otano, I. (Itziar); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María); Perez-Martin, D. (Daniel)
- Deletion of the E3-6.7K/gp19K region reduces the persistence of wild-type adenovirus in a permissive tumor model in Syrian hamsters(Nature, 2009) Lamas, O. (Óscar); Aldabe, R. (Rafael); Alzuguren, P. (Pilar); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María)
- Evaluation of monocytes as carriers for armed oncolytic adenoviruses in murine and Syrian hamster models of cancer(Mary Ann Liebert, 2012) Garcia-Aragoncillo, E. (Eva); Quetglas, J.I. (José Ignacio); Ortiz-de-Solorzano, C. (Carlos); Hervas-Stubbs, S. (Sandra); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Benavides, C. (Carolina); Buñuales, M. (María); RaquelReplication-competent (oncolytic) adenoviruses (OAV) can be adapted as vectors for the delivery of therapeutic genes, with the aim of extending the antitumor effect beyond direct cytolysis. Transgene expression using these vectors is usually intense but short-lived, and repeated administrations are hampered by the rapid appearance of neutralizing antibodies (NAbs). We have studied the performance of monocytes as cell carriers to improve transgene expression in cancer models established in athymic mice and immunocompetent Syrian hamsters. Human and hamster monocytic cell lines (MonoMac6 and HM-1, respectively) were loaded with replication-competent adenovirus-expressing luciferase. Intravenous administration of these cells caused a modest increase in transgene expression in tumor xenografts, but this effect was virtually lost in hamsters. In contrast, intratumoral administration of HM-1 cells allowed repeated cycles of expression and achieved partial protection from NAbs in preimmunized hamsters bearing pancreatic tumors. To explore the therapeutic potential of this approach, HM-1 cells were loaded with a hypoxia-inducible OAV expressing the immunostimulatory cytokine interleukin-12 (IL-12). Three cycles of treatment achieved a significant antitumor effect in the hamster model, and transgene expression was detected following each administration, in contrast with the rapid neutralization of the free virus. We propose monocytes as carriers for multiple intratumoral administrations of armed OAVs.
- Human adenovirus replicates in immunocompetent models of pancreatic cancer in syrian hamsters(Mary Ann Liebert, 2007) Qian, C. (Cheng); Alzuguren, P. (Pilar); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María)
- An oncolytic adenovirus controlled by a modified telomerase promoter is attenuated in telomerase-negative cells, but shows reduced activity in cancer cells(Springer, 2005) Gomar, C. (Celia); Qian, C. (Cheng); Kramer, M.G. (María Gabriela); Farinati, F. (F.); Prieto, J. (Jesús); Bortolanza, S. (Sergia); Hernandez-Alcoceba, R. (Rubén)
- Effect of adenovirus-mediated RNA interference on endogenous microRNAs in a mouse model of multidrug resistance protein 2 gene silencing(American Society for Microbiology, 2006) Aparicio, O. (Óscar); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Vera, M. (María); Razquin, N. (Nerea); Bortolanza, S. (Sergia); Fortes, P. (Puri)RNA interference with viral vectors that express short hairpin RNAs (shRNAs) has emerged as a powerful tool for functional genomics and therapeutic purposes. However, little is known about shRNA in vivo processing, accumulation, functional kinetics, and side effects related to shRNA saturation of the cellular gene silencing machinery. Therefore, we constructed first-generation recombinant adenoviruses encoding different shRNAs against murine ATP-binding cassette multidrug resistance protein 2 (Abcc2), which is involved in liver transport of bilirubin to bile, and analyzed Abcc2 silencing kinetics. C57/BL6 mice injected with these viruses showed significant impairment of Abcc2 function for up to 3 weeks, as reflected by increased serum bilirubin levels. The lack of Abcc2 function correlated with a specific reduction of Abcc2 mRNA and with high levels of processed shRNAs targeting Abcc2. Inhibition was lost at longer times postinfection, correlating with a decrease in the accumulation of processed shRNAs. This finding suggests that a minimal amount of processed shRNAs is required for efficient silencing in vivo. This system was also used to evaluate the effect of shRNA expression on the saturation of silencing factors. Saturation of the cellular silencing processing machinery alters the accumulation and functionality of endogenous microRNAs (miRNAs) and pre-miRNAs. However, expression of functional exogenous shRNAs did not change the levels of endogenous miRNAs or their precursors. In summary, this work shows that adenoviral vectors can deliver sufficient shRNAs to mediate inhibition of gene expression without saturating the silencing machinery.