Introducing Allopurinol to the Medical Treatment of Marfan Syndrome: Advantages, Limitations, and Potential Extension to other Aortopathies

Marfan syndrome (MFS), a multisystemic connective tissue disorder, shows intra- and interfamilial aortopathy variability. More than 3,000 mutations have been reported in the FBN1 gene, which encodes fibrillin-1, a component of microfibrils and elastic fibres. Aortic dilatation mainly affects the aortic root and the ascending aorta. However, dissection of the aortic wall can occur either before or after the aortic arch (type A and type B dissections, respectively). There is no doubt that progress in aortic surgery has significantly improved patients' life expectancy, but conversely, current medical treatment based on beta-blockers (BBs) and angiotensin receptor blockers (ARBs) only slightly slows aortic growth. Aortopathy is the result of multiple defects in cellular and subcellular processes that affect aortic wall cells and extracellular matrix homeostasis and organisation. Pathomechanisms include dysregulated cell signalling, altered mechanotransduction, and oxidative stress. Therefore, it is reasonable to consider a multi-target strategy for medical treatment. Here, we suggest the concurrent administration of allopurinol with current medical treatment. Allopurinol's mode of action is based on its strong antioxidant effects, demonstrated in preclinical assays in different MFS mouse models. Allopurinol is a widely used compound in medical practice for gout, and has been proven safe, economical and effective in other cardiovascular diseases. The recent approval of allopurinol as an orphan drug for the treatment of MFS by the European Medicines Agency (EMA) adds further value to its potential inclusion in standard medical therapy in the near future.