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Inclisiran and the Promise of siRNA

What if, instead of taking medicine daily, treatment could be easily administered only once or twice a year? For many patients with high cholesterol, this could soon become a reality.

Inclisiran, a novel drug for treating severe high cholesterol, uses siRNA (small interfering RNA) technology to produce cholesterol-lowering effects for up to six months after injection (Raal et al.). It has recently been approved for use in the European Union and is currently working its way through FDA approval.

High cholesterol, especially severe forms related to rare genetic mutations, can be a life-threatening ailment that results in arterial blockages from plaque buildup. For many patients, the improved efficacy and convenience of inclisiran would be revolutionary for the management of cholesterol.

The success of inclisiran can be attributed to two key factors. First, while statin drugs (the current standard of care) target cholesterol production in the liver, inclisiran targets a relatively new but well-studied protein called PCSK9. PCSK9 plays an integral role in regulating the removal of cholesterol from the bloodstream; essentially, less PCSK9 corresponds to less cholesterol in the blood. Because statins and inclisiran target such different systems, they can even be used together for increased potency.

The second factor in inclisiran’s success is its siRNA mechanism of action. In order to create proteins, including PCSK9, our cells first use DNA to transcribe a strand of mRNA that encodes the protein’s structure. siRNAs are small RNA molecules that match a specific protein’s mRNA code. Once the siRNA is inside the cell, it is combined with several proteins to create an RNA-induced silencing complex (RISC). RISC then uses the siRNA template to seek out matching mRNAs and disable them. With the mRNA disabled in this way, less target protein (such as PCSK9) is produced (Fitzgerald et al.).

One component contributing to inclisiran’s potency is the chemical modification of the siRNA. While a strand of natural RNA would be quickly degraded by the cell due to its relative instability, inclisiran employs common stabilization methods such as a phosphorothioate backbone, and nucleotides with O-methyl or fluoro substitutions at the 2 position.

A recent study from Alnylam Pharmaceuticals and Harvard Medical School has shed more light on the incredible longevity of siRNA therapeutics (Brown et al.). They focused on contrasting two common delivery methods for siRNAs: GalNAc conjugation and lipid nanoparticles (LNPs). The study attempted to explain why GalNAc siRNA (including inclisiran) has a significantly longer duration of action than LNP siRNA. The authors concluded that GalNAc siRNA is engulfed by liver cells where it accumulates in highly acidic compartments. The siRNA can then slowly leak out of these stored depots to silence protein expression over long timescales (Brown et al.). On the other hand, siRNA delivered via LNPs largely bypasses these compartments, getting delivered more directly into the cell’s cytosol where it is degraded sooner (Brown et al.).

Although the field of siRNA therapeutics is still in its infancy, further studies into the mechanism and applications of siRNA will only serve to demonstrate more of its immense potential. As doctors gain the ability to control protein expression with incredible precision for months at a time, patients may one day be able to trade in their pill organizers for a single shot at their yearly physical.


Works Cited

  1. Brown, Christopher R, et al. “Investigating the Pharmacodynamic Durability of GalNAc–SiRNA Conjugates.” Nucleic Acids Research, vol. 48, no. 21, 2020, pp. 11827–11844., doi:10.1093/nar/gkaa670.

  2. Fitzgerald, Kevin, et al. “A Highly Durable RNAi Therapeutic Inhibitor of PCSK9.” New England Journal of Medicine, vol. 376, no. 18, 2017, doi:10.1056/nejmc1703361.

  3. Raal, Frederick J, et al. “Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia.” The New England Journal of Medicine, vol. 382, 2020, pp. 1520–1530., doi:10.1056/NEJMoa1913805.

  4. National Heart Lung and Blood Institute (NIH), Public domain, via Wikimedia Commons

  5. Singh135, CC BY-SA 4.0 <>, via Wikimedia Commons

Last Fact Checked on May 22nd, 2021.


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