Treatment with siRNA Reduces Plasma Cholesterol in Animal Models

A team of researchers from academia and the drug development industry has created an experimental drug based on a small interfering RNA (siRNA) that dramatically lowered plasma cholesterol levels in rodents and nonhuman primates.

The target of the siRNA was the liver cell protein proprotein convertase subtilisin/kexin type 9 (PCSK9), which regulates low-density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. To target PCSK9 activity in the livers of experimental animals investigators at the University of Texas Southwestern Medical Center (Dallas, TX, USA) in collaboration with Alnylam Pharmaceuticals (Cambridge, MA, USA) and the Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) injected them with siRNAs incorporated into lipidoid nanoparticles.

Results published in the August 11, 2008, online edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50–70%. The reduction in PCSK9 activity was associated with up to a 60% reduction in plasma cholesterol concentrations. In nonhuman primates a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc (averaging 56%), without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for three weeks after a single i.v. administration.

"It is very clear that eliminating this protein has cardiovascular benefits,” said associate author Dr. Jay Horton, professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center. "RNA-based drugs might provide a course of treatment for people whose cholesterol levels are resistant to current drugs, or they might be combined with current drugs.”

Related Links:
University of Texas Southwestern Medical Center
Alnylam Pharmaceuticals
Massachusetts Institute of Technology