title: Manipulating Immune Tolerance with Micro-RNA Regulated Gene Therapy.
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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, Department of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Institute Milan, Italy.
authors.forename: Kevin Scott
authors.initials: KS
authors.lastname: Goudy
authors.forename: Andrea
authors.initials: A
authors.lastname: Annoni
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Roncarolo