AAV-TIMP-1 Mediated Therapy of Aneurysm Formation in a Murine Model of Marfan Syndrome

Background: Marfan syndrome (MFS) is characterized by increased expression of matrix metalloproteinases (MMP) in smooth muscle cells (SMCs) associated with medial elastolysis and aortic aneurysm formation predominantly in the ascending aorta. Long-term expression of MMP antagonist tissue inhibitor of metalloproteinases 1 (TIMP-1) via adeno-associated viruses (AAV-TIMP-1) constitutes a potential treatment option for MFS. Therefore, we aim to provide a causal therapy for the aortopathy of MFS using locally applied gene therapy in a murine model.

Methods: AAV-TIMP-1 and AAV-enhanced green fluorescent protein (AAV-EGFP) vectors were surgically applied circumferentially around the adventitia of the ascending aorta in adult male mgR/mgR Marfan mice. Aortic diameters at the sinotubular junction and the ascending aorta were measured via transthoracic echocardiography on days 0, 15, and 30 after operation.

Results: AAV-TIMP-1-treated mice exhibited significantly reduced aortic dilatation compared with the AAV-EGFP control group at the sinotubular junction and ascending aorta after 30 days. Dilatation of the ascending aorta was 0.08 ± 0.31 mm in the AAV-TIMP-1 group (n = 7) versus 0.78 ± 0.53 mm in the AAV-EGFP group (n = 6), respectively (p = 0.01). Similarly, the sinotubular junction showed significantly less dilatation in the AAV-TIMP-1 group (p = 0.01).

Conclusion: Local administration of AAV-TIMP-1 effectively reduces aneurysm formation in the ascending aorta of fibrillin-1 deficient Marfan mice. Thus, the local overexpression of MMP inhibitors via gene therapy may represent a promising treatment option for the aortic complications of Marfan syndrome.

Publication History

Article published online:
11 February 2025