iPSC-derived VSMC for high-throughput screening of small molecules for aortic aneurysm

Aortic aneurysms (AA) are abnormal aortic dilatations, which remain clinically silent until, inevitably, the aortic wall dissects or ruptures. High blood pressure and genetic mutations in components of the arterial wall are major risk factors, such as mutations in the fibrillin-1 gene in Marfan syndrome. We recently demonstrated that sirtuin-1 (Sirt1), a deacetylase important for cells to cope with metabolic and inflammatory stressors, can be oxidatively modified on critical cysteine thiols nearby its catalytic site; these oxidative modifications inhibit Sirt1 activity, increasing matrix metalloproteinase (MMP2/9) activity and associated elastin fragmentation leading to aortic aneurysm and dissection in Marfan syndrome. Notably, mutating these cysteines, which rendered the mutant Sirt1 resistant to oxidations, restored Sirt1 activity and decreased MMP2/9 activity in vascular smooth muscle (VSMCs) from Marfan mice. Based on this compelling scientific premise, we hypothesize that targeting oxidized Sirt1 could become a novel therapeutic approach to prevent AA and aortic dissections in Marfan syndrome. Through in silico docking analysis and rational drug design of a molecular library comprised of >4,000 compounds, we have identified a lead series of small molecules that showed efficacy in activating Sirt1 in preliminary studies, even in oxidative stress conditions. We will assess the efficacy of our novel class of Sirt1 activators, structurally and mechanistically different than previously developed Sirt1 activators, in inhibiting MMP2/9 hyperactivation and inflammation (VCAM1, p65-NFB) in Marfan VSMCs. We will also generate induced pluripotent stem cell (iPSC)-derived VSMCs, a clinically relevant in vitro model on which to test our small molecules, using peripheral blood mononuclear cells from Marfan patients obtained from the GenTAC/BioLINCC biorepository. These studies are a crucial first step to advance our molecules to in vivo studies and further drug development. If successful, our small molecules Sirt1 activators can become a novel therapy to prevent AA and aortic dissections in individuals at risk, such as Marfan syndrome and related disorders, for which currently no targeted therapy has been developed. Project Number: 1R21HL173511-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Francesca Seta | Institution: BOSTON UNIVERSITY MEDICAL CAMPUS, BOSTON, MA | Award Amount: $122,625 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZHL1 CSR-K (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HL17351101A1