Researchers in a collaborative study evaluate DT-109, an orally deliverable tripeptide, for its effects on advanced atherosclerosis and vascular calcification in cynomolgus monkeys. Administered daily alongside a high-cholesterol diet, DT-109 significantly reduces lesion formation, inflammatory signaling, and arterial calcification while promoting smooth muscle cell contractile marker expression. These findings suggest a multifaceted therapeutic approach to combat cardiovascular disease by targeting inflammasome pathways and plaque stability.

Key points

• Orally administered DT-109 (Gly-Gly-Leu) peptide at 150 mg/kg/day in cynomolgus monkeys.
• Five-month treatment with a cholesterol-rich diet showed significant reductions in aortic and coronary lesion size.
• DT-109 downregulates pro-inflammatory genes NLRP3, AIM2, CASP1 and oxidative stress markers NCF2, NCF4.
• Treatment reduces vascular calcification and macrophage content while increasing SMC contractile markers ACTA2, CNN1, TAGLN.
• In vitro assays confirm DT-109 inhibits NLRP3 inflammasome activation and smooth muscle cell calcification.

Why it matters: These results demonstrate a novel peptide-based strategy that combines anti-inflammatory and anti-calcific actions to address advanced atherosclerosis, a leading cause of cardiovascular mortality. By demonstrating efficacy in primate models, DT-109 bridges the gap between rodent research and human application, offering a promising route to more effective, orally available therapies that can regress plaque and restore vascular function.