M Noormalal (1), A. Matzen (1), S. Hille (1), P. Shetty (1), T. Bozoglu (2), A. H. Wagner (3), R. Arif (3), C. Kupatt (2), D. Frank (1), O.J. Müller (1), A. Kliesow Remes (1)

1: Department of Internal Medicine III, University of Kiel, and German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany; 2: Department of Internal Medicine I, Klinikum rechts der Isar, Munich and German Centre for Cardiovascular Research, Partner Site Munich, Germany; 3: Department of Internal Medicine III, University Hospital Heidelberg and German Centre for Cardiovascular Research, Partner Site Heidelberg/Mannheim, Germany

Background

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by defects in elastic fiber integrity, leading to a markedly increased risk of thoracic aortic aneurysm formation. Affected individuals often die at a young age. Dysregulated expression of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) has been implicated as a key factor contributing to extracellular matrix degradation and structural instability of the aortic wall in MFS.

Methods and Results

Marfan mice were systemically injected with G2ᶜᴺᴺ-tagged Adeno-associated virus (AAV) 9 for vascular transduction, encoding either TIMP-1 or EGFP as control. Four weeks later, echocardiographic assessment of aortic diameter was performed and thoracic aortae were taken for further analysis regarding MMP activity, elastin structure, and tight junction expression in the intima.

Gelatin zymography revealed a marked reduction of MMP activity following AAV-mediated TIMP-1 overexpression. Furthermore, elastin degradation was significantly reduced in the treatment group. Echocardiographic measurements showed that mice receiving the TIMP-1 AAV presented with significantly reduced aortic diameter.

Conclusion

Here we show that AAV9-mediated overexpression of TIMP-1 in aortic cells results in the restoration of elastin fiber architecture, thereby enhancing vascular stability and reducing aneurysm size in a murine model of Marfan syndrome. These findings highlight the potential of this strategy to be further developed as a promising novel therapeutic approach for the treatment of MFS.