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Researchers Develop DNA-encoded PCSK9 Inhibitors to Regulate Cholesterol Levels in Bloodstream

The Wistar Institute researchers have developed novel synthetic DNA-encoded Monoclonal Antibodies (DMAbs) directed against PCSK9, a protein key to regulating cholesterol levels in the bloodstream.

A preclinical study showed a significant cholesterol decrease, helping for the development of this approach as a simple, less frequent and cost-effective therapy.

Elevated, Low-Density Lipoprotein Cholesterol (LDL-C) is one of the major reasons for cardiovascular disease.

Strains are effective and widely used cholesterol-lowering medications, but they are associated with a number of side effects that have prompted development of alternative treatment strategies.

This has resulted in reduced degradation of LDL-C receptors on liver cells and increased cholesterol clearance from blood circulation.

Any therapy based on recombinant monoclonal antibodies faces challenges of production among other issues as molecules may be difficult to manufacture and require multiple administrations.

Anti-PCSK9 therapy presents an important opportunity for development of alternative approaches, possibly expanding options for such therapies.

Synthetic DNA will be delivered by intramuscular injection and encode the genetic instructions for the body to make its own functional monoclonal antibodies.

This will bypass bioprocess and manufacturing factory approaches. It showcases that engineered DMAbs may be developed as a new option for coronary artery disease.

The researchers tested expression and activity of the DMAbs targeting PCSK9 in mice.

 A single intramuscular administration drove robust antibody expression within days and for up to two months, resulting in a substantial increase in the presence of LDL-C receptors on liver cells.

This in turn resulted in a significant decrease in total cholesterol and non-High-Density Lipoprotein Cholesterol (non-HDL-C), an important parameter for evaluating cardiovascular risk.

These results, findings help to support the flexibility and versatality of the DMAb platform as a next generation approach that can be optimised for a wide host of applications.

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