Life exists in a delicate balance that must be constantly maintained in a narrow range. Too much or too little of any chemical in our bodies can end our lives. The entire game of medicine is a struggle to find ways to keep everything in homeostasis. A new drug recently approved in the United Kingdom may prove to be game-changing in one of medicine’s battles to maintain homeostasis.

Heart disease is always at or near the top of the leading causes of death for humans. One key player in the battle to fight heart disease is cholesterol. High levels of low-density lipoprotein, or LDL, often called “bad” cholesterol, are associated with increased heart disease and stroke risks. The medical community already has an arsenal of weapons to battle high LDL levels. Statins are commonly used along with changes in diet and exercise and even monoclonal antibodies.

The monoclonal antibody therapy targets an enzyme called proprotein convertase subtilisin/kexin type 9 or PCSK9. The PCSK9 enzyme plays a role in removing LDL receptors from a cell’s membrane. LDL receptors function to bind with LDL particles floating in the extracellular fluid and bring them into a cell for processing. This lowers the concentration of LDL in our extracellular fluids. Since PCSK9 removes these LDL receptors from your cells, blocking it would increase the number of LDL receptors and force cells to bring in more LDL, thus lowering LDL levels. Likewise, if PCSK9 were overactive and removed too many LDL receptors, this would raise LDL concentrations in our extracellular fluids. Researchers working at UT-Southwestern in the early 2000s showed that people with very low levels of LDL in their blood had mutations in the PCSK9 gene that reduced its activity. The link between PCSK9 and LDL concentrations is apparent.

The newly approved UK drug called inclisiran goes after PCSK9 also but in a unique way. This drug works through a process known as RNA interference. If you can block the activity of PCSK9, then you can make cells take in more LDL from the extracellular fluid, thus lowering LDL concentrations. The goal is still the same, but instead of trying to bind PCSK9 after it is produced, as monoclonal antibodies do, why not block it from being made in the first place?

RNA interference works by silencing the gene transcripts that have the instructions to make PCSK9. If you block the production of PCSK9, then it cannot remove your cell’s LDL receptors. With those LDL receptors still in place, they do their job and take more LDL out of your extracellular fluids. Clinical trials have shown that inclisiran can cut LDL levels in your blood by 50%, and it is only two subcutaneous injections each year. Much better than daily medications or biweekly monoclonal antibody injections.

This treatment is not yet approved by the U.S. Food and Drug Administration, but perhaps it will be soon. Then the medical community will have a new “genetic” weapon in their daily battles to achieve LDL balance for patients. Google “RNAi: Slicing, dicing and serving your cells” and you will find a short TED-Ed video that explains RNA interference in more detail.

Dr. Jack Brown is the Paris Junior College Science Division chairman. His science articles are published every Sunday. 

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