Small Interfering RNAs (siRNAs)

Small interfering RNAs (siRNAs) are short (~21 nucleotides), double-stranded RNA molecules that can be administered to patients to degrade specific messenger RNAs (mRNAs). They do so by a mechanism called RNA interference (RNAi), which cells use in the context of their antiviral defenses. Briefly, one of the two strands of a siRNA is selected by a host protein, and this strand is used to recognize (and cleave) mRNAs with perfect sequence complementarity. Thus, RNAi provides a potent and predictable way to silence the expression of theoretically any desired gene, acting at the posttranscriptional level. However, it took 20 years for the first siRNA biotherapeutic to reach the market. This chapter will explain the many challenges that basic and applied researchers had to face to move RNAi into the clinic, with delivery into cells being one of the major struggles. This problem was solved by the use of either lipid nanoparticles (patisiran) or chemically modified siRNAs conjugated to the ligand of an abundant cell surface receptor (givosiran, lumasiran, inclisiran, vutrisiran, nedosiran). Despite the latter strategy having proven useful, with several products now in the market, its use is currently restricted to the liver. Nevertheless, several clinical trials using siRNAs directed to other cell types are ongoing. The RNAi revolution might be just starting.