Improving siRNA Bio-Distribution and Minimizing Side Effects

Abstract

The RNA interference (RNAi) is a biological process by which a double stranded RNA (dsRNA also called small interfering RNA - siRNA) triggers the sequence-dependent degradation of a target RNA within the cellular environment. Thus siRNAs can be used to combat the expression of deleterious gene(s) causing disease or to destroy invading pathogen RNAs. Despite their enormous therapeutic potential, the use of siRNA as drugs presents two major problems: the difficulties to identify optimal delivery systems and the possible induction of different unwanted side effects. In this review, after presenting an overview about the mechanisms ruling the process of RNAi, we focus the attention on the description of the strategies developed to optimise systemic siRNA delivery; in this sense, considerations about the attempts to improve siRNA stability in the biological environment, the development of synthetic vectors for siRNA delivery, the siRNA bio-distribution and pharmacokinetics together with the selection of siRNA targeted delivery systems, are discussed. Since in the optimisation of the siRNA delivery systems the minimization of siRNA side effects should not be neglected, in the last part of the review we consider the problems related to the possible induction of siRNA mediated side effects focusing on the so called microRNA like off-targeting.

Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA

“…For example, sequence alterations by mutation in the antisense strand may result in non-recognition of the homologous mRNA by the loaded RISC. The design parameters that determine the effectiveness of RNAi includes thermodynamic stability, the number of nucleotides in the siRNA sequence the% of GC residues, the secondary structure of the RNA, the number of sites with single nucleotide polymorphism (SNP) and the number of repeats (132). The use of commonly available computational design tools allows the synthesis of potentially effective siRNA sequences.…”

Against the clock towards new Ebola virus therapies

“…Combinatorial use of different siRNAs targeting three RNA-encoding EBOV proteins (L polymerase, membrane-associated VP24 and polymerase complex VP35) has proven to be successful to inhibit EBOV in guinea pigs (Geisbert et al, 2006). However, siRNA-based therapies have been reported to present potentially serious off-targeting effects and unwanted induction of the interferon response, thus reducing the chances of becoming good antiviral candidates in the near future (Scaggiante et al, 2011). Such is the case of the commercial siRNA cocktail TKMEbola, which was undergoing clinical trials during 2014 but was eventually put on partial hold due to its concerning side effects (Tekmira, 2014).…”

Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

“…MicroRNAs are small (approx 18-25 nt) non-coding double-stranded RNAs with the capacity to regulate the expression of target genes mainly by impairing mRNA translation, but also by inducing mRNA degradation [62,63] and by affecting chromatin remodeling [64] . The miRNA pathway starts with the transcription of a long precursor defined primary miRNA (pri-miRNA), which is subsequently processed (pre-miRNA) in the nucleus by a cellular enzyme called Drosha.…”