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Updated: May 21, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies
Lorenzo Da Dalt1, Andrea Baragetti1, Giuseppe Danilo Norata1
1Department of Pharmacological Sciences 'Rodolfo Paoletti', University of Milan, Milano, Italy.
Introduction:
PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases LDLR recycling on the surface of hepatocytes, which promotes the catabolism of LDL particles. PCSK9 can be synthesized in extra-hepatic tissues, including in the brain, the pancreas, and the heart, and in immune cells. It is of interest to understand whether the extra-hepatic effects observed when PCSK9 is genetically inhibited by naturally occurring mutations are also recapitulated by pharmacology.
Area Covered:
Genetics studies reported an increased risk of developing new-onset diabetes, ectopic adiposity, and reduced immune-inflammatory responses with PCSK9 deficiency. However, these aspects were not observed in clinical trials and data from real-world medicine with monoclonal antibodies (mAbs) and gene silencing approaches targeting PCSK9.
Expert Opinion:
It is possible that the biological adaptations occurring when PCSK9 is inhibited lifelong, as in the case of genetic studies, could explain the discrepancy with the data obtained by clinical studies testing the pharmacological inhibition of PCSK9. Also, PCSK9 mAbs have been in use for 12 years; thus, probably, in this time window, a pharmacological reduction of circulating PCSK9 up to 80-90% does not lead to changes other than the impressive reduction in LDL-C and in CVD events.
Insights
Genetic PCSK9 deficiency is linked to diabetes and immune changes, but these effects aren't seen with PCSK9-targeting drugs. Lifelong genetic inhibition may cause different adaptations than short-term pharmacology.
Area of Science:
- Cardiovascular medicine
- Genetics
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition increases LDL receptor recycling, enhancing LDL particle clearance.
- PCSK9 is synthesized in various tissues, including the brain, pancreas, heart, and immune cells.
- Understanding extra-hepatic PCSK9 effects from genetic vs. pharmacological inhibition is crucial.
Purpose of the Study:
- To investigate discrepancies between genetic and pharmacological PCSK9 inhibition effects.
- To determine if extra-hepatic effects observed in genetic studies are replicated by PCSK9-targeting therapies.
Main Methods:
- Review of genetic studies on PCSK9 deficiency.
- Analysis of clinical trial data and real-world evidence for PCSK9 monoclonal antibodies (mAbs) and gene silencing.
- Comparison of lifelong genetic inhibition versus short-term pharmacological inhibition.
Main Results:
- Genetic PCSK9 deficiency is associated with increased risk of new-onset diabetes, ectopic adiposity, and reduced immune-inflammatory responses.
- These adverse effects were not observed in clinical trials using PCSK9 mAbs or gene silencing.
- Pharmacological PCSK9 inhibition (up to 12 years) primarily leads to significant LDL-C reduction and decreased cardiovascular events.
Conclusions:
- Lifelong biological adaptations from genetic PCSK9 inhibition may differ from short-term pharmacological effects.
- Current PCSK9 pharmacology effectively reduces LDL-C and cardiovascular risk without apparent extra-hepatic adverse effects within the observed timeframe.
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