Translational Medicine: Towards Gene Therapy of Marfan Syndrome

Abstract

Marfan syndrome (MFS) is one of the most common inherited disorders of connective tissue caused by mutations of the fibrillin-1 gene (FBN1). Vascular abnormalities, such as the enlargement of the aorta with the risk of life-threatening rupture are frequently observed. However, current treatment is limited and therapeutic options focus solely on symptomatic therapy. Gene therapy focuses on genetically modifying cells to produce a therapeutic effect and may be a promising treatment option for MFS. Here, we first provide an overview of the historical background and characterization of MFS. Subsequently, we summarise current gene therapy options and possible translational concepts for this inherited disorder that affects connective tissue.

Keywords: TGF-β; aorta; aortic surgery; gene therapy; marfan syndrome; translational therapy.

Figure 1

Schematic mechanism of action for antisense, siRNA, and transcription factor decoy oligodeoxynucleotides. Antisense ODNs bind to their target messenger RNA (mRNA) and inhibit or alter translation, e.g., via steric hindrance, splicing alterations, or the initiation of target degradation. The activity of small interfering RNAs (siRNA) in RNA interference (a biological process in which RNA molecules inhibit gene expression) is dependent on its binding ability to the RNA-induced silencing complex (RISC). The binding of the double-stranded siRNA to RISC is followed by unwinding and cleavage of the sense strand, which binds to its target mRNA and induces mRNA cleavage. The mechanism of the action of transcription factor decoy ODN is distinct from antisense and siRNA ODNs. Decoy ODNs are targeted to inhibit the binding of transcription factor (TF) to their cognate promoter binding sites in the genome. Reprinted from Biochem Pharmacol 144, Hecker and Wagner [39], Copyright 2017, with permission from Elsevier.

Figure 2

AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome. Reprinted from Cardiovasc Res 117, Remes et al. [14], Copyright 2021, with permission from Oxford University Press.

Figure 3

Recent concepts and preclinical approaches to treat Marfan syndrome (AP-1; activator protein-1; PAI-1, plasminogen activator inhibitor-1; TIMP-1, tissue inhibitor of metalloproteinase-1).