A Novel Micro-RNA (miRNA) Regulated Transgene Expression System: Implications for Gene Therapy

Gene therapy is the manipulation of gene expression, or products, by an exogenously expressed gene. This type of therapy has implications for correcting, or compensating for deregulated genes involved in disease, such as hemophilia or cystic fibrosis. Immune inactivation of transgene expression is however a common problem in current gene therapy models.

In a recent issue of Nature Medicine, Brown and colleagues devise a novel vector system regulated by tissue specific miRNAs to alleviate immune inactivation. miRNAs are small RNA molecules that control the tissue specificity of gene expression by regulating mRNA degradation rates and translation. They are themselves expressed in a tissue specific manner and can be exploited to regulate a theraputic gene of interest (ie. silence expression of a gene in one cell type but not another).

The exact mechanism by which an immune response to therapeutic gene products is mounted is unknown; Brown postulates leaky gene expression within immune effector cells ultimately leads to their activation. By utilizing the tissue specificity of miRNA expression, the authors were able to construct gene vectors with miRNA binding sites capable of silencing reporter gene expression specifically in hematopoetic cells (immune cell lineage) and not those of other lineages in vitro.

Using a mouse model, the authors demonstrate that the hematopoetic specific miRNA binding site prevents reporter gene expression in splenic leukocytes, but not in surrounding fibroblasts. Similar results were also obtained within the lung, gut and thymus. The presence of the miRNA binding site also led to sustained gene expression when compared to controls, indicating immune inactivation had not occurred.

Brown believes that this technology has the potential to produce specific gene expression in a wide array of cells, overcoming the limitations of tissue specific promoters and states, "this will raise the overall production of therapeutic protein and could improve clinical outcome".