The European Medicines Agency (EMA) has designated allopurinol as the first orphan drug for the treatment of Marfan syndrome, marking a significant milestone for patients with this rare genetic connective tissue disorder. Marfan syndrome, which affects approximately 7 in 100,000 people in the European Union, currently has no cure and primarily impacts the cardiovascular, skeletal, and ocular systems.
This orphan drug designation represents an important step forward in developing treatments for this serious condition, which can lead to life-threatening aortic aneurysms and dissections. The designation does not establish the drug as safe or effective for this indication but recognizes that it meets the European Commission's criteria for orphan drug status, providing pharmaceutical companies with favorable conditions to develop and market treatments for rare diseases.
From Gout Treatment to Vascular Protection
Allopurinol, widely used for decades to treat gout, has shown promising results in preclinical studies for preventing and treating the aortic aneurysms characteristic of Marfan syndrome. The drug works by inhibiting the enzyme xanthine oxidoreductase (XOR), which generates uric acid and reactive oxygen species. Researchers have discovered that XOR is altered in the aortas of both Marfan syndrome patients and mouse models of the disease.
A research team from the University of Barcelona, the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), and the Networking Biomedical Research Centre on Rare Diseases (CIBERER) has been at the forefront of investigating allopurinol's potential new application. The group, led by Professor Gustavo Egea from the UB's Faculty of Medicine and Health Sciences, has conducted extensive trials on animal models.
"Treatment with allopurinol, which acts as a powerful antioxidant, has been shown to halt and prevent the progression and onset of aneurysms and aortic dissections," explained Egea. The research team worked in close collaboration with postdoctoral researcher Isaac Rodríguez-Rovira and CIBERER researcher Victoria Campuzano.
Understanding Marfan Syndrome
Marfan syndrome is caused by mutations in the FBN1 gene, which encodes fibrillin-1, a protein essential for the structural integrity of many tissues in the body as it forms part of elastic fibers. The disease exhibits remarkable clinical variability among patients, with over 3,000 different mutations identified, even within the same family carrying an identical genetic variant.
This chronically debilitating condition leads to serious vascular alterations, ranging from abnormal dilation of the aorta to potentially fatal aortic dissection and rupture. Non-fatal manifestations include respiratory complications like pneumothorax and sleep apnea, ocular disorders such as blindness due to lens dislocation, and musculoskeletal impairments including muscular and joint flaccidity and tall stature.
Current Treatment Limitations
Currently, there is no approved curative treatment for Marfan syndrome. Existing pharmacological therapy is palliative and primarily relies on beta-blockers and antihypertensives/angiotensin II receptor antagonists. However, the effectiveness of these treatments remains highly limited, often necessitating surgical intervention on a dilated aorta (preventive surgery) or an already dissected aorta (emergency repair surgery), both of which carry significant risks.
The Promise of Drug Repurposing
The repurposing of allopurinol for cardiovascular treatment in Marfan syndrome is particularly promising due to its established safety profile, extensive clinical history, and low cost. These factors make it an attractive option not only for Marfan syndrome but potentially for other vascular diseases as well.
"In addition to its pharmacological benefits, allopurinol is also a safe, cheap, and well-known clinical drug," noted Rodríguez-Rovira. "This makes its repurposing especially attractive because of its extensive clinical profile, pharmacological safety record, and low cost."
Next Steps
While the research has shown promising results in animal models, the next crucial phase will involve international clinical trials in patients. These studies will be essential to determine the drug's efficacy and safety in humans with Marfan syndrome and to potentially secure full approval for this new indication.
The orphan drug designation by the EMA provides incentives for further development, including protocol assistance, reduced regulatory fees, and market exclusivity upon approval. These benefits aim to encourage pharmaceutical companies to invest in developing treatments for rare diseases that might otherwise be commercially unviable.
For the Marfan syndrome community, this development represents hope for a new treatment option that could potentially reduce the need for high-risk surgeries and improve quality of life for those affected by this rare genetic disorder.
