RNA Interference Technologies and Therapeutics

Abstract

RNA interference (RNAi) is a natural cellular process that regulates gene expression by a highly precise mechanism of sequence-directed gene silencing at the stage of translation by degrading specific messenger RNAs or blocking translation. In recent years, the use of RNAi for therapeutic applications has gained considerable momentum. It has been suggested that most of the novel disease-associated targets that have been identified are not 'druggable' with conventional approaches. However, any disease-causing gene and any cell type or tissue can potentially be targeted with RNAi. This review focuses on the current knowledge of RNAi mechanisms and the safety issues associated with its potential use in a therapeutic setting. Some of the most important aspects to consider when working towards the application of RNAi-based products in a clinical setting have been related to achieving high efficacies and enhanced stability profiles through a careful design of the nucleic acid sequence and the introduction of chemical modifications, but most of all, to developing improved delivery systems, both viral and non-viral. These new delivery systems allow for these products to reach the desired target cells, tissues or organs in a highly specific manner and after administration of the lowest possible doses. Various routes of application and target locations are currently being addressed in order to develop effective delivery systems for different targets and pathologies, including infectious pathologies, genetic pathologies and diseases associated with dysregulation of endogenous microRNAs. As with any new technology, several challenges and important aspects to be considered have risen on the road to clinical intervention, e.g. correct design of preclinical toxicology studies, regulatory concerns, and intellectual property protection. The main advantages related to the use of RNAi-based products in a clinical setting, and the latest clinical and preclinical studies using these compounds, are reviewed.

miR-126 enhances the sensitivity of non-small cell lung cancer cells to anticancer agents by targeting vascular endothelial growth factor A

“…Due to the development of various methods of miRNA delivery [40], miRNAs are being developed for new therapeutics. VEGF is expressed in 50%-95% of NSCLC patients and is related to poor prognosis and metastatic potential.…”

Novel modulators of senescence, aging, and longevity: Small non-coding RNAs enter the stage

“…Finally, small non-coding RNAs and RNAi have already been introduced as promising novel drugs in preclinical and clinical trials against various diseases (Blenkiron and Miska, 2007;Lopez-Fraga et al, 2009;Mishra et al, 2009b;Nakasa et al, 2009;Takeshita et al, 2009;Zhang, 2009). The power of small ncRNAs and their derivatives as putative therapeutic molecules together with the still scarce functional knowledge about non-coding RNAs in regard to aging gives all reason to expect many surprises for basic and biomedical aging research in regard to nonconding RNAs.…”

High‐throughput RNAi screening to dissect cellular pathways: A how‐to guide

“…Used in combination with drugs, systematic RNAi approaches can help unravel the mode of action of drugs, identify enhancers of the therapeutic mechanism or shed light on putative markers of resistance of a certain treatment [52][53][54]. Thus, RNAi screens might help in the near future to improve the treatment of highly resistant and aggressive tumors by identifying targets for efficient cotreatments [55][56][57][58]. …”