AUTHOR=Goudy Kevin S., Annoni Andrea , Naldini Luigi , Roncarolo Maria Grazia TITLE=Manipulating Immune Tolerance with Micro-RNA Regulated Gene Therapy JOURNAL=Frontiers in Microbiology VOLUME=2 YEAR=2011 URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2011.00221 DOI=10.3389/fmicb.2011.00221 ISSN=1664-302X ABSTRACT=

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.