Prospects for Therapeutic Targeting of MicroRNAs in Human Immunological Diseases

Abstract

MicroRNAs (miRNAs) are endogenous oligo-ribonucleotides with exciting therapeutic potential. Early studies have established a clear role for miRNAs in leukocyte biology. The first miRNA-based therapy, Miravirsen, is now in Phase 2 clinical trials, making the reality of these therapies undeniable. The capacity for miRNAs to fine-tune inflammatory signaling make them attractive treatment targets for immunological diseases. Nonetheless, the degree of redundancy among miRNAs, coupled with promiscuity of miRNA binding sites in the transcriptome, require consideration when designing miRNA-directed interventions. Altered miRNA expression occurs across a range of inflammatory conditions including inflammatory bowel disease, arthritis and diabetes. To date, however, there have been very few studies successfully treating murine models of immunological diseases with miRNA-based approaches. While discussing recent studies targeting miRNAs to treat immunological conditions, we will also reflect on risks of miRNA-targeting and showcase some newer delivery systems that may improve the pharmacological profile of this class of therapeutics.

MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage

“…Loss-of-function experiments have demonstrated the broad importance of miRNAs in development, including the developmental programs of B cells, T cells, and other leukocytes. 69 Moreover, specific “immuno-miRNAs,” including miR-181a-2-3p, have been shown to regulate lymphocyte differentiation and function. 70 Although platelets are anuclear, they contain cytoplasmic mRNA, carry out protein translation, and express over 280 miRNAs, and platelet miRNA-mRNA coexpression profiles have been correlated with platelet reactivity.…”

Mitochondrial Epigenetics and Environmental Exposure

“…The therapeutic potential of miRNA or RNA-based therapies has been proposed for treatment of many disease and cancers, including miR-122 therapy for the treatment of immunological diseases [100]. However, to date, there have been no clinical trial of such drugs targeting the mitochondria.…”

Shifting from Correlation to Causation: Challenges for the Future of Unbiased Molecular Studies in Inflammatory Lung Disease

“…In rabbits, controlled mechanical ventilation (CMV) causes injury to the diaphragm but not to soleus myofibers (9). In patients, CMV produced diaphragmatic atrophy without impacting extradiaphragmatic muscles (10).…”

“…miRNAs have the potential to bind hundreds of mRNA targets, and hence are hypothesized to be able to fine-tune complex regulatory networks by targeting multiple genes at once (7). miRNAs have been implicated in modulating the inflammatory response contributing to multiple diseases (8,9). As chronic inflammation is central to the pathogenesis of COPD, it is important to understand how miRNAs influence the aberrant inflammatory response in this disease.…”