Minimal-invasive therapy of Marfan syndrome: Local AAV mediated inhibition of thoracal aneurysm formation and aortic dissection

• Applicant: Privatdozent Dr. Rawa Arif
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508473803

Marfan syndrome (MFS) is the most common inherited genetic disorder of connective tissue, which has a fatal course due to its aortic manifestation. Acute dissection of the ascending aorta is the main cause of premature death, with the estimated life expectancy in untreated patients with the 4th decade of age, which necessitates prophylactic aortic root and ascending aortic replacement in 80% of the patients. Alterations of TGF-β metabolism and secondary deleterious effects of matrix fragmentation by inflammation and structural changes of smooth muscle cells (SMCs) are two of the major pathophysiological factors in the development and progression of MFS in which the transcription factor AP-1 and matrix metalloproteinases (MMPs) and inhibitor TIMP-1 play a key role.The current conservative treatment comprises betablocker and additive losartan therapy, however, without causal options and prevention of the surgical intervention of the aortic root. Aortic root replacement implies intervention of the native aortic valve, which usually is preserved. If valve sparing fails, valve replacement with a mechanical prosthesis is the most common alternative, thus reducing the quality-of-life due need of lifelong oral anticoagulation therapy with a Vitamin K antagonist. After successful transduction tissue-specific adeno-associated virus (AAVs) facilitate the long-term overexpression of protective extracellular matrix (EM) proteins and inhibition of pathologically abundant transcription factors. Thereby, transduced endothelial cells and SMCs allow the inhibition of the proteolytic MMPs. This project aims to prevent the formation of aortic aneurysms and dissections in a murine model of MFS. By introducing a novel translational minimal-invasive approach we aim to develop a possible alternative treatment option to conventional surgery. We apply two (1, 2) gene therapies: By AAV induced inhibition of (1) AP-1 and overexpression (2) of TIMP-1 –delivered through an absorbable alginate – we aim to restore the homeostasis of the dysregulated EM of the aortic media. The findings of the animal studies are then validated in human aortic tissue in vitro.Here, a cardiac surgeon with activity in basic science, surgery, and conservative treatment – supported by experienced cardiovascular researchers – makes use of alternative gene therapies in a translational minimal-invasive murine model aiming to prevent the aneurysm formation and expanding the life-expectancy in MFS.

• DFG Programme: Research Grants