Mechanism of action of inclisiran (leqvio)

Inclisiran and Physiology

The emerging small interfering RNA (siRNA) technology offers a unique opportunity for the inhibition of particular genes within cells, which allows for the exploration of gene functions, the control of gene expression, and the potential development of treatments for various conditions. This technology takes advantage of the RNA interference (RNAi) pathway that naturally occurs in living organisms to silence genes after transcription.

The RNAi pathway is triggered by double-stranded RNA (dsRNA) molecules in the cell, which can either be introduced externally or produced internally. An enzyme known as Dicer breaks down these long dsRNA molecules into shorter fragments of 20-30 nucleotides called small interfering RNAs (siRNAs). Each siRNA is composed of two strands: a guide strand and a passenger strand.

The guide strand, also referred to as the antisense strand, is critical in the RNAi process. It corresponds to the target mRNA sequence intended for silencing. After siRNA is created, the guide strand becomes part of the RNA-induced silencing complex (RISC). The RISC then utilizes the guide strand to identify and attach to the target mRNA. Once attached, an enzyme in the RISC called Argonaute splits the target mRNA, effectively ceasing its expression.

The passenger strand, or the sense strand, is the counterpart to the guide strand. Following siRNA creation, the passenger strand is typically either destroyed or ejected from the RISC complex. The role of the protein PCSK9 in the metabolism of LDL cholesterol was previously discussed.

Mechanism of Action of Inclisiran

Inclisiran and other small interfering RNA (siRNA) inhibitors of PCSK9 synthesis represent an innovative class of agents that reduce lipids. They use RNA interference (RNAi) technology to target and disintegrate PCSK9 messenger RNA (mRNA). This action leads to a decrease in PCSK9 protein synthesis, ultimately resulting in lower LDL cholesterol (LDL-C) levels.

The mechanism of action of siRNA inhibitors of PCSK9 synthesis includes the following stages:

  1. The siRNA molecule, matching a specific segment of the PCSK9 mRNA, is transported into the target cells, which are usually hepatocytes.
  2. Once inside the cell, the siRNA combines with several proteins to form the RNA-induced silencing complex (RISC).
  3. The RISC complex, guided by the siRNA, connects with the complementary PCSK9 mRNA. This connection leads to the splitting and degradation of the target mRNA.
  4. The degradation of mRNA results in the inhibition of PCSK9 protein translation, reducing PCSK9 synthesis.
  5. With the decrease in PCSK9 levels, there is less destruction of LDL-R on the surfaces of hepatocytes. This leads to an increase in LDL-R expression and activity, allowing for improved clearance of circulating LDL-C.

Inclisiran and Clinical Use

Inclisiran has shown to be highly effective in reducing LDL cholesterol (LDL-C) levels. By silencing the PCSK9 gene, inclisiran enables an increase in the number of LDL receptors on the liver cells. These LDL receptors are responsible for the clearance of LDL-C from the blood, and their increased number and activity facilitate greater absorption of LDL-C, thus reducing the circulating LDL-C levels.

Inclisiran has been developed as a subcutaneous injection, with a dosing regimen typically consisting of an initial dose, a second dose after three months, and subsequent doses every six months. This infrequent dosing regimen makes inclisiran a convenient option for patients who have difficulty adhering to daily medication schedules.

Nevertheless, as with any medication, inclisiran does have potential side effects. Some of the common adverse effects include injection site reactions, fatigue, and musculoskeletal pain. However, these side effects are generally mild and transient.

While inclisiran is a promising therapeutic option, it should be noted that it is not a stand-alone treatment. It is used as an adjunct to diet and maximally tolerated statin therapy in patients who require additional LDL-C lowering due to a high risk of atherosclerotic cardiovascular disease.

In summary, inclisiran leverages siRNA technology to silence the PCSK9 gene, reducing the production of the PCSK9 protein, and thus leading to lower LDL cholesterol levels. Its potential for improving patient outcomes in the treatment of high cholesterol and associated conditions remains a promising area of ongoing research and clinical trials.

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