Exploration of cyclophilin A antibody anti-eCypA as a new approach in the treatment of marfan syndrome

Abstract Background Marfan syndrome (MFS) is a rare genetic disease characterized by the development of aortic aneurysms with a high risk of complications such as aortic dissection. Current treatment options are limited to advanced surgical procedures with the risk of complications. Thus, alternative, less invasive therapeutic approaches are required. Previous studies suggested that the selective inhibition of extracellular cyclophilin A (CypA), a danger-associated molecular pattern (DAMP) secreted in response to vascular stress, reduces the formation of abdominal aortic aneurysms. Therefore, we aimed to explore the effects of selectively inhibiting CypA on aortic aneurysm formation and wall architecture in MFS using fibrillin-1-deficient mice (mgR/mgR), a well-characterized murine model for MFS. Methods Over the course of four weeks, male mgR/mgR mice were subcutaneously injected with the CypA antibody anti-eCypA or an idiotypic IgG control. Ultrasound examination was performed on the baseline and after two and four weeks of treatment. Moreover, we assessed the diameter of the thoracic aorta using innovative MRI scans four weeks after the beginning of the treatment. Furthermore, the aortic wall constitution was evaluated by performing immunhistochemistry, zymography and elastin staining of aortic tissue. Results The analysis of elastin breaks by Elastin van Gieson staining in the aortic wall of the mice showed a significant decrease of elastin breaks in treatment compared to control group. While analysis of the ultrasound images showed an enlarged aortic diameter in both groups after four weeks, the increase in the treated group was less pronounced than in the control group. Interestingly, two weeks of treatment did not lead to a strong increase in diameter in either group, suggesting the main formation of aneurysms develops rather between weeks two and four. Importantly, the results of the MRI scan analysis were consistent with the ultrasound findings. Notably, we found marked decrease in gelatinase activity following treatment and a reduction in EMMPRIN and VCAM1 expression in the aortic wall in mice subjected to anti-eCypA treatment. Conclusion Our results suggest a beneficial effect of anti-eCypA in the remodelling of the aortic wall in MFS, demanding further exploration with a larger animal cohort. Ultimately, CypA inhibition employing anti-eCypA may present a valuable alternative to more invasive surgical strategies for the treatment of MFS.