siRNAs with promising therapeutic potential

Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs

Literature - N Engl J Med 2017; 376:4-7 - N Engl J Med 2017

Managing cholesterol levels is the standard of care for prevention of atherosclerosis. Until recently, small-molecule drugs -most of them statins- were the main treatment of choice to lower cholesterol. This area is changing, as currently, monoclonal antibodies targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) such as alirocumab and evolocumab, have been shown to also achieve substantial cholesterol reduction and are being introduced in clinical setting.

Furthermore, another new promising area of cholesterol-lowering is emerging at the moment. This includes the development of small interfering RNAs (siRNAs) that are able to specifically and robustly lower LDL-c levels by targeting the PCSK9 gene in hepatocytes. Hepatocytes are primarily responsible for cholesterol clearance. The specificity to only target hepatocytes is achieved by conjugation of the siRNA to GalNAc (N-acetylgalactosamine) [1], which recognizes the asialoglycoprotein receptor (ASGPR) that is highly expressed on the surface of hepatocytes.

Conjugated siRNAs can be quickly synthesized and the cost may be equal to the development of small molecule drugs. However, the relative simplicity of the manufacturing process and the temperature stability might eventually make this class of therapeutics widely available for a broad population. The structure and chemical composition of the siRNA such as sugars, bases and the phosphate backbone, single-stranded or duplex structure and the presence of a targeting ligand, play an essential role in its potency and is the key in the extraordinary long activity of inclisiran, an LDL-c-lowering siRNA that is in phase 3 development.

An siRNA consists of two strands, a guide and passenger. The guide strand recognizes the target gene, while the passenger strand supports loading of the siRNA into the RNA-induced silencing complex (RISC). After loading, the passenger strand is degraded and the guide strand together with the RISC complex, targets mRNA for degradation and thereby gene silencing.

Although first early clinical trials with siRNAs failed to show clinical efficacy, chemical optimization now revealed the extremely potent and durable effective inclisiran. It needs a single subcutaneous injection and lowers a patient’s LDL-c level for 6 months. This is in contrast to the currently available statins and PCSK9 antibodies, that need to be administered every day and every 2 to 4 weeks, respectively.

Inclisiran targets the 3’UTR of PCSK9 and chemical optimization compared to the first drugs includes increased stability; siRNAs were differently modified to prevent degradation by exonucleases and endonucleases [2]. Furthermore, an extra deoxythymidine included in the middle or the sense strand, accelerates degradation of the passenger strand, or both strands, after incorporation into RISC. In addition, the 3’end of the passenger strand is conjugated to GalNAc, yielding specificity.


1. Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 2014; 136: 16958-61.

2. International nonproprietary names for pharmaceutical substances (INN). WHO Drug Information 2016; 30(3): 504 (http:// www .who .int/ medicines/ publications/ drug information/ innlists/ RL76 .pdf?ua=1).

Find this article online at NEJM

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