RNA interference: a potent tool for gene-specific therapeutics

Abstract

RNA interference (RNAi) is a process through which double-stranded RNA induces the activation of cellular pathways, leading to potent and selective silencing of genes with homology to the double strand. Much excitement surrounding small interfering RNA (siRNA)-mediated therapeutics arises from the fact that this approach overcomes many of the shortcomings previously experienced with approaches such as antibodies, antisense oligonucleotides and pharmacological inhibitors. Induction of RNAi through administration of siRNA has been successfully used in treatment of hepatitis, viral infections, and cancer. In this review we will present a brief history of RNAi, methods of inducing RNAi, application of RNAi in the therapeutic setting, and the possibilities of using this highly promising approach in the context of transplantation.

Figure 1

Induction of RNA interference. (A) Natural gene silencing by long double‐stranded RNA (dsRNA). Upon viral infection or the presence of other dsRNA transducted intracellularly, an innate defense system is activated that causes the sequential degradation of the dsRNA by the type III endonuclease DICER. This endonuclease subsequently cleaves the dsRNA into 21 nucleotide double‐stranded fragments. These fragments then associate with the RNA‐induced silencing complex (RISC) complex and induce cleavage of endogenous mRNA transcripts in a sequence‐ and length‐ specific manner. However, long dsRNA also activates 2′5 oligosynthetase which induces nonspecific interferon response and global shutdown of protein synthesis. (B) Artificial gene silencing through siRNA. To take advantage of the gene‐silencing effect while circumventing nonspecific cellular effects, synthetic dsRNA of 21 nucleotides are transfected into the cell. This small interfering RNA (siRNA) is not recognized by DICER or 2′5 oligosynthetase, but instead directly binds the RISC complex that subsequently induces selective silencing of endogenous transcripts.