Molecular Therapy: Methods & Clinical Development (Mar 2024)

Regnase-1 overexpression as a therapeutic approach of Marfan syndrome

  • Marie Noormalal,
  • Nesrin Schmiedel,
  • Tarik Bozoglu,
  • Andrea Matzen,
  • Susanne Hille,
  • Dima Ibrahim Basha,
  • Prithviraj Manohar Vijaya Shetty,
  • Anja Wolf,
  • Marcin Zaradzki,
  • Rawa Arif,
  • Thomas Pühler,
  • Georg Lutter,
  • Andreas H. Wagner,
  • Christian Kupatt,
  • Derk Frank,
  • Norbert Frey,
  • Anca Remes,
  • Oliver J. Müller

Journal volume & issue
Vol. 32, no. 1
p. 101163

Abstract

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Rupture or dissection of thoracic aortic aneurysms is still the leading cause of death for patients diagnosed with Marfan syndrome. Inflammation and matrix digestion regulated by matrix metalloproteases (MMPs) play a major role in the pathological remodeling of the aortic media. Regnase-1 is an endoribonuclease shown to cleave the mRNA of proinflammatory cytokines, such as interleukin-6. Considering the major anti-inflammatory effects of regnase-1, here, we aimed to determine whether adeno-associated virus (AAV)–mediated vascular overexpression of the protein could provide protection from the development and progression of aortic aneurysms in Marfan syndrome. The overexpression of regnase-1 resulted in a marked decrease in inflammatory parameters and elastin degradation in aortic smooth muscle cells in vitro. Intravenous injection of a vascular-targeted AAV vector resulted in the efficient transduction of the aortic wall and overexpression of regnase-1 in a murine model of Marfan syndrome, associated with lower circulating levels of proinflammatory cytokines and decreased MMP expression and activity. Regnase-1 overexpression strongly improved elastin architecture in the media and reduced aortic diameter at distinct locations. Therefore, AAV-mediated regnase-1 overexpression may represent a novel gene therapy approach for inhibiting aortic aneurysms in Marfan syndrome.

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