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siRNA and RNAi optimization

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The discovery and examination of the posttranscriptional gene regulatory mechanism known as RNA interference (RNAi) contributed to the identification of small interfering RNA (siRNA) and the comprehension of its enormous potential for clinical purposes. Theoretically, the ability of specific target gene downregulation makes the RNAi pathway an appealing solution for several diseases. Despite numerous hurdles resulting from the inherent properties of siRNA molecule and proper delivery to the target tissue, more than 50 RNA‐based drugs are currently under clinical testing. In this work, we analyze the recent literature in the optimization of siRNA molecules. In detail, we focused on describing the most recent advances of siRNA field aimed at optimize siRNA pharmacokinetic properties. Special attention has been given in describing the impact of RNA modifications in the potential off‐target effects (OTEs) such as saturation of the RNAi machinery, passenger strand‐mediated silencing, immunostimulation, and miRNA‐like OTEs as well as to recent developments on the delivery issue. The novel delivery systems and modified siRNA provide significant steps toward the development of reliable siRNA molecules for therapeutic use. WIREs RNA 2016, 7:316–329. doi: 10.1002/wrna.1337 This article is categorized under: RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action RNA in Disease and Development > RNA in Disease
Benefits and drawbacks of small interfering RNA (siRNA)‐based therapeutics. In addition to important unwanted off‐target effects such as the upregulation and downregulation of thousands of unrelated genes, during the attempt of developing RNA interference (RNAi)‐based therapeutics some intrinsic siRNA limitations have been identified. Upon entering the bloodstream the siRNA molecules are promptly degraded and eliminated; the action of ribonucleases and reticuloendothelial system (RES) compromises its bioavailability under physiological conditions. Furthermore, the siRNA hydrophilicity, high molecular weight, and polyanionic nature restrict its passive diffusion across cellular membranes. Even though all these serious issues, the siRNA properties can be adjusted in terms of gene silencing abilities (potency, specificity, and efficacy). The ability of siRNA molecule to target any disease‐related gene offers a valuable option to block the production of all those undruggable proteins, not responding to traditional therapy, at the messenger RNA level.
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Chemical structures of modified backbones used in small interfering RNA (siRNA).
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Ago2 diagram and small interfering RNA (siRNA) molecule. Top strand is the passenger or sense and bottom strand is the guide or antisense. The passenger strand during RNA‐induced silencing complex (RISC) maturation is nicked and degraded, whereas the guide strand is retained and serves as complementary sequence for the identification of the target messenger RNA.
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RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry
RNA in Disease and Development > RNA in Disease
Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action

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