An apolipoprotein C-II (apoC-II) mimetic peptide known as D6PV lowers triglyceride levels by activating lipoprotein lipase (LPL) and antagonizing the triglyceride-raising effects of apoC-III, according to a new study published in Science Translational Medicine. D6PV increases triglyceride lipolysis in mouse models of hypertriglyceridaemia (HTG) and shows good bioavailability in non-human primates, indicating its potential as a treatment for patients with HTG.

Credit: JUAN GAERTNER/SCIENCE PHOTO LIBRARY

Given that patients with elevated plasma triglyceride levels are at increased risk of cardiovascular disease, novel therapies targeting HTG are needed. Anna Wolska (NHLBI, USA) and colleagues designed a peptide called D6PV that has dual apoC-II mimetic and apoC-III antagonist activity. “The inspiration for designing the D6PV peptide was from a simulation on the Anton 2 supercomputer, which was specifically created to perform 30 molecular dynamics simulations,” comments senior investigator Alan Remaley (NHLBI, USA).

The efficacy of D6PV was first tested in plasma from humans with HTG. D6PV was a more potent ex vivo activator of lipolysis than full-length apoC-II in plasma from patients with apoC-II deficiency and also increased LPL-dependent lipolysis in plasma from patients with moderate HTG. To test the hypothesis that this effect might be associated with antagonism of apoC-III, LPL was added to pooled human HTG plasma and incubated with D6PV. Addition of apoC-III to human HTG plasma blunted the lipolysis of triglycerides, but D6PV prevented this inhibition by displacing apoC-III from lipoproteins.

In apoC-II-deficient mice, intraperitoneal delivery of D6PV resulted in a rapid reduction in plasma triglyceride levels by 70% after 1 h and by 85% after 3 h. Furthermore, transgenic mice expressing human APOC3 (hAPOC3-Tg mice) treated with D6PV had an 80% decrease in plasma triglyceride levels after 3 h and an 85% reduction in total plasma apoC-III levels, in addition to reduced apoC-III bound to VLDL, LDL and HDL particles. D6PV also reduced LDL levels by 10% in hAPOC3-Tg mice lacking the LDL receptor. These findings support a mechanism whereby D6PV can lower triglyceride levels by displacing apoC-III from triglyceride-rich lipoproteins, independently of its direct effect of stimulating LPL.

Finally, the bioavailability of D6PV was tested in both mice and non-human primates. D6PV had a subcutaneous bioavailability of 80% and an extended terminal half-life of 42–50 h in non-human primates, which translates to a half-life of 3–4 days in humans using allometric scaling.

These findings support a mechanism whereby D6PV can lower triglyceride levels by displacing apoC-III from triglyceride-rich lipoproteins

“Our research is still in early stages, but it is possible that this investigational therapy could be developed as a once-a-week injectable chronic therapy for apoC-II-deficient patients or patients with HTG,” highlights senior investigator Matt Devalaraja (Corvidia Therapeutics, USA). “We look forward to continuing our research on D6PV and our partnership with the NHLBI.”