A novel processing pathway for microRNA molecules with therapeutic potential

The abnormal expression of cellular proteins is a defining feature of various diseases. Proteins are translated from specific messenger RNA (mRNA) coding sequences. Therefore, the ability to regulate or block specific mRNAs can be exploited to allow control of aberrant protein expression during disease. Inhibition of protein expression can be achieved using small RNA molecules, such as microRNAs (miRNAs), which target and interfere with specific mRNAs by blocking or degrading them. In the future, this could permit the regulation of disease-specific protein levels in patients.

Viruses are biological vehicles which have evolved to deliver their genome to specific cell types. In this paper, published in the February 2012 issue of Molecular Therapy, the authors engineered a virus called VSV, previously been shown to be safe in pre-clinical studies, to contain the miRNA sequence, miR-124. The authors showed that VSV-miR-124 produced large quantities of miR-124 following infection of cells and that miR-124 successfully mediated repression of its target. Interestingly, the mechanisms of miRNA processing from RNA viruses used in this study were shown to be novel, which will undoubtedly trigger new research questions and possibilities for the field. Importantly, when VSV-miR-124 was delivered intranasally, miR-124 levels in the lung persisted, even following virus clearance. Furthermore, there was repression of miR-124 targets, demonstrating that this proof-of-principle study is functional in vivo.

There is great potential for the translation of this technology for the treatment of acute disease conditions. However, the approach can be limited by off-target interference with mRNAs which code for normal cellular proteins. Additionally, achieving targeted delivery following intravenous injection will be a major challenge. It will be important to further refine both miRNA target specificity and tissue-specific delivery in order to minimize off-target toxicity and improve the clinical utility of miRNA technology.