Digesting dietary miRNA therapeutics

Hippocrates famously advised, " Let food be thy medicine and thy medicine be thy food. " Numerous plant-derived compounds are used as cancer therapeutics including antimitotics, topoisomerase inhibitors, and kinase inhibitors. Here we will review emerging evidence suggesting that diet derived small RNAs may be an inexpenisive, non-invasive and affordable way to deliver cancer treatments. RNA interference (RNAi), the use of short double-stranded RNA sequences to silence endogenous genes is emerging as the next generation of therapeutics. A well-designed RNAi molecule is able to differentially silence a mutated oncogene with just a single mutated base, leaving the wild-type unaffected. Further, due to the use of intrinsic cellular mechanisms for gene silencing, RNAi exerts an amplified stoichiometric effect, suppressing expression of thousands of mRNA transcripts per RNAi molecule. The challenge with the use of RNAi therapeutics remains their efficient uptake and transportation to target cells. Various delivery techniques are being investigated including viral delivery, engineered nanoparticles and modified nucleic acid chemistry. Each method faces a unique set of challenges including efficiency, safety, and immunogenicity. Utilization of therapeutics by the oral route promises low costs, minimal invasiveness, and high compliance, making this the holy grail of delivery methods. In 2012, a study demonstrated a dietary microRNA (miRNA) from rice was packaged and systemically circulated in consuming mice to silence a liver gene [1]. Plant miRNAs contain a unique 2'-O-methylation on the ribose of the 3' nucleotide, which was used to distinguish the plant-derived miRNAs from endogenous miRNAs. The authors postulated that this modification promotes stability of dietary small RNAs. In the last several years, numerous reports have failed to establish dietary delivery of miRNAs as a general means of gene regulation in healthy consumers [2]. However, our group has reported dietary regimes and pharmacological methods to enhance detection of dietary miRNA in mice serum [3]. Our work implies that high doses and certain gut pathologies enhance uptake of dietary small RNAs. In other studies, mice fed large doses of synthetic plant-modified miRNAs appear to have therapeutic potential [4]. Using a mouse model of colon cancer, a cocktail of tumor-suppressing miRNAs with plant-based chemistries were fed to mice and significantly decreased tumor burden. We posit this therapy was successful due to the enhanced uptake capabilities in the impaired gut. Additional studies have shown that oral administration of high dosages of small RNAs halt the replication of the influenza virus in mice [5]. Taken …