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.
Highlights
A major obstacle for achieving therapeutic efficacy when using in vivo gene therapy is the development of an immune response toward the transgene since pathogenic immune responses can lead to the clearance of transgene-expressing cells
We focus on the use of vector modification with micro-RNA targets to regulate transgene expression and how they can be used with other layers of vector modification to promote transgene tolerance
Among the Treg subpopulations are the naturally occurring Treg, which are differentiated in the thymus, and the induced Treg which are induced in the periphery, are phenotypically similar and have similar regulatory properties; the relative contribution of iTreg and nTreg in regulating immune responses in different disease states is subject to ongoing discussions
Summary
A major obstacle for achieving therapeutic efficacy when using in vivo gene therapy is the development of an immune response toward the transgene since pathogenic immune responses can lead to the clearance of transgene-expressing cells. PROMOTER AND VECTOR MODULATION TO REDUCE TRANSGENE IMMUNITY Tissue-specific promoters that restrict transgene expression to a targeted cell type have been widely employed in gene therapy to avoid immune responses.
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