%A Goudy,Kevin %A Annoni,Andrea %A Naldini,Luigi %A Roncarolo,Maria Grazia %D 2011 %J Frontiers in Microbiology %C %F %G English %K Gene Therapy,Hepatocytes,Liver,micro-RNA,regulatory cells,tolerance,transgene,Treg %Q %R 10.3389/fmicb.2011.00221 %W %L %M %P %7 %8 2011-November-14 %9 Mini Review %+ Prof Maria Grazia Roncarolo,San Raffaele Institute,Via Olgettina 58,200063,Milan,Italy,mg1@stanford.edu %+ Prof Maria Grazia Roncarolo,Università Vita-Salute San Raffaele,Milan,Italy,mg1@stanford.edu %# %! Transgene Tolerance Using micro-RNA %* %< %T Manipulating Immune Tolerance with Micro-RNA Regulated Gene Therapy %U https://www.frontiersin.org/articles/10.3389/fmicb.2011.00221 %V 2 %0 JOURNAL ARTICLE %@ 1664-302X %X The success of in vivo gene therapy greatly depends on the ability to control the immune response toward the therapeutic transgene. Over the last decade several vector-based and pharmacological approaches have been explored to control the immune-mediated clearance of transgene-expressing cells after viral delivery. One important outcome from these studies is the concept that expression of a transgene in tolerance-promoting organs, such as the liver and tolerogenic antigen-presenting cells, can help safeguard transgene-expressing cells from immune-mediated clearance. Gene therapists are now manipulating vectors to target naturally occurring tolerogenic properties of the body by: (i) incorporating tissue/cell specific promoters for targeted expression, (ii) using viral-capsid engineering to alter tropism and avoid pre-existing immunity, and (iii) regulating cell and activation dependent expression by including micro-RNA (miR) targets into expression cassettes. The combination of these three layers of vector regulation greatly enhances the targeting of tolerogenic cells and limits off-target expression of the transgene, which can lead to the induction of transgene-specific pathogenic effector T cells. In this review, we discuss the application of using miR transgene regulation to generate tolerogenic responses and speculate on possible mechanisms used by the liver to induce the transgene-specific regulatory T cells.