Small interfering RNA from the lab discovery to patients' recovery.

In 1998, the RNA interference discovery by Fire and Mello revolutionized the scientific and therapeutic world. They showed that small double-stranded RNAs, the siRNAs, were capable of selectively silencing the expression of a targeted gene by degrading its mRNA. Very quickly, it appeared that the use of this natural mechanism was an excellent way to develop new therapeutics, due to its specificity at low doses. However, one major hurdle lies in the delivery into the targeted cells, given that the different extracellular and intracellular barriers of the organism coupled with the physico-chemical characteristics of siRNA do not allow an efficient and safe administration. The development of nanotechnologies has made it possible to counteract these hurdles by vectorizing the siRNA in a vector composed of cationic lipids or polymers, or to chemically modify it by conjugation to a molecule. This has enabled the first clinical developments of siRNAs to begin very quickly after their discovery, for the treatment of various acquired or hereditary pathologies. In 2018, the first siRNA-containing drug was approved by the FDA and the EMA for the treatment of an inherited metabolic disease, the hereditary transthyretin amyloidosis. In this review, we discuss the different barriers to the siRNA after systemic administration and how vectorization or chemical modifications lead to avoid it. We describe some interesting clinical developments and finally, we present the future perspectives.