Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended t...Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed cases.It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression.We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods.There is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and progression.In this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic target.Indeed,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo.In parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug delivery.This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA.In summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.展开更多
基金supported by the National Institute of Health(NIH)grants R01HL133665(to L.-W.G.),R01HL143469R01HL129785(to K.C.K,S.G.,and L.-W.G.)+2 种基金R01HL162895(to B.W.)R01HL132395 and 1S10RR027333(to J.A.H.)Overseas Research Fellowships,The Uehara Memorial Foundation in Japan(to T.S.).
文摘Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed cases.It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression.We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods.There is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and progression.In this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic target.Indeed,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo.In parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug delivery.This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA.In summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.
