Long‐term miR‐29b suppression reduces aneurysm formation in a Marfan mouse model

Aortic root aneurysm formation and subsequent dissection and/or rupture remain the leading cause of death in patients with Marfan syndrome. Our laboratory has reported that miR‐29b participates in aortic root/ascending aorta extracellular matrix remodeling during early aneurysm formation in Fbn1 (C1039G/+) Marfan mice. Herein, we sought to determine whether miR‐29b suppression can reduce aneurysm formation long‐term. Fbn1 (C1039G/+) Marfan mice were treated with retro‐orbital LNA‐anti‐miR‐29b inhibitor or scrambled‐control‐miR before aneurysms develop either (1) a single dose prenatally (pregnant Fbn1 (C1039G/+) mice at 14.5 days post‐coitum) (n = 8–10, each group) or (2) postnatally every other week, from 2 to 22 weeks of age, and sacrificed at 24 weeks (n = 8–10, each group). To determine if miR‐29b blockade was beneficial even after aneurysms develop, a third group of animals were treated every other week, starting at 8 weeks of age, until sacrificed (n = 4–6, each group). miR‐29b inhibition resulted in aneurysm reduction, increased elastogenesis, decreased matrix metalloproteinase activity and decreased elastin breakdown. Prenatal LNA‐anti‐miR‐29b inhibitor treatment decreased aneurysm formation up to age 32 weeks, whereas postnatal treatment was effective up to 16 weeks. miR‐29b blockade did not slow aortic growth once aneurysms already developed. Systemic miR‐29b inhibition significantly reduces aneurysm development long‐term in a Marfan mouse model. Drug administration during aortic wall embryologic development appears fundamental. miR‐29b suppression could be a potential therapeutic target for reducing aneurysm formation in Marfan syndrome patients.