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The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market

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A Correction to this article was published on 07 February 2018

This article has been updated

Abstract

Ten years after Fire and Melo’s Nobel Prize for discovery of gene silencing by double-stranded RNA, a remarkable progress was achieved in RNA interference (RNAi). Changes in the chemical structure of synthetic oligonucleotides make them more stable and specific, and new delivery strategies became progressively available. The attention of pharmaceutical industry rapidly turned to RNAi, as an opportunity to explore new drug targets. This review addresses nine small-interfering RNAs (siRNAs) and one unique microRNA (miRNA) inhibitor, which entered the phase 2–3 clinical trials. The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3). Regarding miRNAs, their content can be down- or up-regulated, by using miRNA inhibitors (AntimiRs) or miRNA mimics. Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development.

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Change history

  • 07 February 2018

    The published article contains an error in Figure 5. The term “Atu027” should be substituted by “Patisiran” in figure and legend.

Abbreviations

LNA:

Locked nucleic acid

LNP:

Lipid nanoparticle

LODER:

LOcal Drug EluteR

PEG:

Polyethylene glycol

PLGA:

poly(lactic-co-glycolic) acid

RISC:

RNA-induced silencing complex

RNAi:

RNA interference

SNALPs:

Stable nucleic acid lipid particles

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  1. Technology for Gene Therapy Laboratory, ASS 128, ICC Sul, University of Brasília–UnB, Campus Darcy Ribeiro, FAV., Brasília, DF, 70910-970, Brazil

    Ricardo Titze-de-Almeida & Simoneide Souza Titze-de-Almeida

  2. Av. Pedro Severino Junior, 366, sala 45 e 46 – Vila Guarani, São Paulo, SP, 04310-060, Brazil

    Catherine David

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Titze-de-Almeida, R., David, C. & Titze-de-Almeida, S.S. The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. Pharm Res 34, 1339–1363 (2017). https://doi.org/10.1007/s11095-017-2134-2

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